Tyrosine kinase inhibitors

ABSTRACT

The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.

BACKGROUND OF THE INVENTION

The present invention relates to compounds which inhibit, regulateand/or modulate tyrosine kinase signal transduction, compositions whichcontain these compounds, and methods of using them to treat tyrosinekinase-dependent diseases and conditions, such as angiogenesis, cancer,tumor growth, atherosclerosis, age related macular degeneration,diabetic retinopathy, inflammatory diseases, and the like in mammals.

Tyrosine kinases are a class of enzymes that catalyze the transfer ofthe terminal phosphate of adenosine triphosphate to tyrosine residues inprotein substrates, as described in U.S. Pat. No. 6,245,759 B1 (herebyincorporated by reference).

Angiogenesis is characterized by excessive activity of vascularendothelial growth factor (VEGF) (as described in U.S. Pat. No.6,245,759 B1). KDR mediates the mitogenic function of VEGF whereas Flt-1appears to modulate non-mitogenic functions such as those associatedwith cellular adhesion. Inhibiting KDR thus modulates the level ofmitogenic VEGF activity. In fact, tumor growth has been shown to besusceptible to the antiangiogenic effects of VEGF receptor antagonists.(Kim et al., Nature 362, pp. 841-844, 1993).

Solid tumors can therefore be treated by tyrosine kinase inhibitorssince these tumors depend on angiogenesis for the formation of the bloodvessels necessary to support their growth. These solid tumors includehistiocytic lymphoma, cancers of the brain, genitourinary tract,lymphatic system, stomach, larynx and lung, including lungadenocarcinoma and small cell lung cancer. Additional examples includecancers in which overexpression or activation of Raf-activatingoncogenes (e.g., K-ras, erb-B) is observed. Such cancers includepancreatic and breast carcinoma. Accordingly, inhibitors of thesetyrosine kinases are useful for the prevention and treatment ofproliferative diseases dependent on these enzymes.

The angiogenic activity of VEGF is not limited to tumors. VEGF accountsfor most of the angiogenic activity produced in or near the retina indiabetic retinopathy. This vascular growth in the retina leads to visualdegeneration culminating in blindness. Ocular VEGF mRNA and protein areelevated by conditions such as retinal vein occlusion in primates anddecreased pO₂ levels in mice that lead to neovascularization.Intraocular injections of anti-VEGF monoclonal antibodies or VEGFreceptor immunofusions inhibit ocular neovascularization in both primateand rodent models. Regardless of the cause of induction of VEGF in humandiabetic retinopathy, inhibition of ocular VEGF is useful in treatingthe disease.

Expression of VEGF is also significantly increased in hypoxic regions ofanimal and human tumors adjacent to areas of necrosis. VEGF is alsoupregulated by the expression of the oncogenes ras, raf, src and mutantp53 (all of which are relevant to targeting cancer). Monoclonalanti-VEGF antibodies inhibit the growth of human tumors in nude mice.Although these same tumor cells continue to express VEGF in culture, theantibodies do not diminish their mitotic rate. Thus tumor-derived VEGFdoes not function as an autocrine mitogenic factor. Therefore, VEGFcontributes to tumor growth in vivo by promoting angiogenesis throughits paracrine vascular endothelial cell chemotactic and mitogenicactivities. These monoclonal antibodies also inhibit the growth oftypically less well vascularized human colon cancers in athymic mice anddecrease the number of tumors arising from inoculated cells.

Inhibition of KDR or Flt-1 is implicated in pathological angiogenesis,and these receptors are useful in the treatment of diseases in whichangiogenesis is part of the overall pathology, e.g., inflammation,diabetic retinal vascularization, as well as various forms of cancersince tumor growth is known to be dependent on angiogenesis. (Weidner etal., N. Engl. J. Med., 324, pp. 1-8, 1991).

SUMMARY OF THE INVENTION

The present invention relates to indolylindazole compounds that arecapable of inhibiting, modulating and/or regulating signal transductionof both receptor-type and non-receptor type tyrosine kinases.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition of kinasesand are illustrated by a compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

-   W is N or C;-   X═Y is C═N, N═C, or C═C;-   a is 0 or 1;-   b is 0 or 1;-   m is 0, 1,or 2;-   t is 1,2,or 3;-   R¹, R² and R⁵ are independently selected from:    -   1) H,    -   2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,    -   3) (C═O)_(a)O_(b)aryl,    -   4) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl,    -   5) (C═O)_(a)O_(b)C₂-C₁₀ alkynyl,    -   6) CO₂H,    -   7) halo,    -   8) OH,    -   9) O_(b)C₁-C₆ perfluoroalkyl,    -   10) (C═O)_(a)NR⁷R⁸,    -   11) CN,    -   12) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,    -   13) (C═O)_(a)O_(b)heterocyclyl,    -   14) SO₂NR⁷R⁸, and    -   15) SO₂C₁-C₁₀ alkyl,        said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl        is optionally substituted with one or more substituents selected        from R⁶;-   R³ is selected from:    -   1) H,    -   2) (C═O)O_(a)C₁-C₆ alkyl,    -   3) (C═O)O_(a)aryl,    -   4) C₁-C₆ alkyl,    -   5) SO₂R^(a), and    -   6) aryl;-   R⁴ is selected from:    -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,    -   2) (C═O)_(a)O_(b)aryl,    -   3) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl,    -   4) (C═O)_(a)O_(b)C₂-C₁₀ alkynyl,    -   5) CO₂H,    -   6) halo,    -   7) OH,    -   8) O_(b)C₁-C₆ perfluoroalkyl,    -   9) (C═O)_(a)NR⁷R⁸,    -   10) CN,    -   11) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,    -   12) (C═O)_(a)O_(b)heterocyclyl,    -   13) SO₂NR⁷R⁸, and    -   14) SO₂C₁-C₁₀ alkyl,        said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl        is optionally substituted with one or more substituents selected        from R⁶;-   R⁶ is:    -   1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,    -   2) (C═O)_(a)O_(b)aryl,    -   3) C₂-C₁₀ alkenyl,    -   4) C₂-C₁₀ alkynyl,    -   5) (C═O)_(a)O_(b)heterocyclyl,    -   6) CO₂H,    -   7) halo,    -   8) CN,    -   9) OH,    -   10) O_(b)C₁-C₆ perfluoroalkyl,    -   11) O_(a)(C═O)_(b)NR⁷R⁸,    -   12) oxo,    -   13) CHO,    -   14) (N═O)R⁷R⁸, or    -   15) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        optionally substituted with one or more substituents selected        from R^(6a);-   R^(6a) is selected from:    -   1) (C═O)_(r)O_(s)(C₁-C₁₀ )alkyl, wherein r and s are        independently 0 or 1,    -   2) O_(r)(C₁-C₃)perfluoroalkyl, wherein r is 0 or 1,    -   3) (C₀-C₆)alkylene-S(O)_(m)R^(a), wherein m is 0, 1, or 2,    -   4) oxo,    -   5) OH,    -   6) halo,    -   7) CN,    -   8) (C₂-C₁₀ )alkenyl,    -   9) (C₂-C₁₀ )alkynyl,    -   10) (C₃-C₆)cycloalkyl,    -   11) (C₀-C₆)alkylene-aryl,    -   12) (C₀-C₆)alkylene-heterocyclyl,    -   13) (C₀-C₆)alkylene-N(R^(b))₂,    -   14) C(O)R^(a),    -   15) (C₀-C₆)alkylene-CO₂R^(a),    -   16) C(O)H,    -   17) (C₀-C₆)alkylene-CO₂H, and    -   18) C(O)N(R^(b))₂,        said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl        is optionally substituted with up to three substituents selected        from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆        alkyl, oxo, and N(R^(b))₂;-   R⁷ and R⁸ are independently selected from:    -   1) H,    -   2) (C═O)O_(b)C₁-C₁₀ alkyl,    -   3) (C═O)O_(b)C₃-C₈ cycloalkyl,    -   4) (C═O)O_(b)aryl,    -   5) (C═O)O_(b)heterocyclyl,    -   6) C₁-C₁₀ alkyl,    -   7) aryl,    -   8) C₂-C₁₀ alkenyl,    -   9) C₂-C₁₀ alkynyl,    -   10) heterocyclyl,    -   11) C₃-C₈ cycloalkyl,    -   12) SO₂R^(a), and    -   13) (C═O)NR^(b) ₂,        said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl        is optionally substituted with one or more substituents selected        from R^(6a), or-   R⁷ and R⁸ can be taken together with the nitrogen to which they are    attached to form a monocyclic or bicyclic heterocycle with 5-7    members in each ring and optionally containing, in addition to the    nitrogen, one or two additional heteroatoms selected from N, O and    S, said monocylcic or bicyclic heterocycle optionally substituted    with one or more substituents selected from R^(6a);-   R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl; and-   R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl, (C₃-C₆)cycloalkyl,    (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a).

A second embodiment of the invention is a compound of Formula I, or apharmaceutically acceptable salt or stereoisomer thereof, wherein

A further embodiment of the present invention is illustrated by acompound of Formula I, or a pharmaceutically acceptable salt orstereoisomer thereof, with Z as defined immediately above, wherein

-   a is 0 or 1;-   b is 0 or 1;and-   t is 1 or 2;-   R¹, R² and R⁵ are independently selected from:    -   1) H,    -   2) (C═O)_(a)O_(b)C₁-C₆ alkyl,    -   3) (C═O)_(a)O_(b)aryl,    -   4) (C═O)_(a)O_(b)C₂-C₆ alkenyl,    -   5) (C═O)_(a)O_(b)C₂-C₆ alkynyl,    -   6) CO₂H,    -   7) halo,    -   8) OH,    -   9) O_(b)C₁-C₃ perfluoroalkyl,    -   10) (C═O)_(a)NR⁷R⁸,    -   11)CN,    -   12) (C═O)_(a)O_(b)C₃-C₆ cycloalkyl,    -   13) (C═O)_(a)O_(b)heterocyclyl,    -   14) SO₂NR⁷R⁸, and    -   15) SO₂C₁-C₆ alkyl,        said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl        is optionally substituted with one or more substituents selected        from R⁶;-   R⁴ is selected from:    -   1) (C═O)_(a)O_(b)C₁-C₆ alkyl,    -   2) (C═O)_(a)O_(b)aryl,    -   3) (C═O)_(a)O_(b)C₂-C₆ alkenyl,    -   4) (C═O)_(a)O_(b)C₂-C₆ alkynyl,    -   5) CO₂H,    -   6) halo,    -   7) OH,    -   8) O_(b)C₁-C₃ perfluoroalkyl,    -   9) (C═O)_(a)NR⁷R⁸,    -   10) CN,    -   11) (C═O)_(a)O_(b)C₃-C₆ cycloalkyl,    -   12) (C═O)_(a)O_(b)heterocyclyl,    -   13) SO₂NR⁷R⁸, and    -   14)SO₂C₁-C₆ alkyl,        said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl        is optionally substituted with one or more substituents selected        from R⁶;-   R⁶ is:    -   1) (C═O)_(a)O_(b)C₁-C₆ alkyl,    -   2) (C═O)_(a)O_(b)aryl,    -   3) C₂-C₆ alkenyl,    -   4) C₂-C₆ alkynyl,    -   5) (C═O)_(a)O_(b)heterocyclyl,    -   6) CO₂H,    -   7) halo,    -   8) CN,    -   9) OH,    -   10) O_(b)C₁-C₃ perfluoroalkyl,    -   11) O_(a)(C═O)_(b)NR⁷R⁸,    -   12) oxo,    -   13)CHO,    -   14) (N═O)R⁷R⁸, or    -   15) (C═O)_(a)O_(b)C₃-C₆ cycloalkyl,        said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl        is optionally substituted with one or more substituents selcted        from R^(6a);-   R^(6a) is selected from:    -   1) (C═O)_(r)O_(s)(C₁-C₆)alkyl, wherein r ands are independently        0 or 1,    -   2) O_(r)(C₁-C₃)perfluoroalkyl, wherein r is 0 or 1,    -   3) (C₀-C₆)alkylene-S(O)_(m)R^(a), wherein m is 0, 1, or 2,    -   4) oxo,    -   5) OH,    -   6) halo,    -   7) CN,    -   8) (C₂-C₆)alkenyl,    -   9) (C₂-C₆)alkynyl,    -   10) (C₃-C₆)cycloalkyl,    -   11) (C₀-C₆)alkylene-aryl,    -   12) (C₀-C₆)alkylene-heterocyclyl,    -   13) (C₀-C₆)alkylene-N(R^(b))₂,    -   14) C(O)R^(a),    -   15) (C₀-C₆)alkylene-CO₂R^(a),    -   16) C(O)H, and    -   17) (C₀-C₆)alkylene-CO₂H,        said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl        is optionally substituted with up to three substituents selected        from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆        alkyl, oxo, and N(R^(b))₂; and-   R⁷ and R⁸ are independently selected from:    -   1) H,    -   2) (C═O)O_(b)C₁-C₆ alkyl,    -   3) (C═O)O_(b)C₃-C₆ cycloalkyl,    -   4) (C═O)O_(b)aryl,    -   5) (C═O)O_(b)heterocyclyl,    -   6) C₁-C₆ alkyl,    -   7) aryl,    -   8) C₂-C₆ alkenyl,    -   9) C₂-C₆ alkynyl,    -   10) heterocyclyl,    -   11) C₃-C₆ cycloalkyl,    -   12) SO₂R^(a), and    -   13) (C═O)NR^(b) ₂,        said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl        is optionally substituted with one or more substituents selected        from R6^(a), or-   R⁷ and R⁸ can be taken together with the nitrogen to which they are    attached to form a monocyclic or bicyclic heterocycle with 5-7    members in each ring and optionally containing, in addition to the    nitrogen, one or two additional heteroatoms selected from N, O and    S, said monocylcic or bicyclic heterocycle optionally substituted    with one or more substituents selected from R^(6a);-   R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl; and-   R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl, (C₃-C₆)cycloalkyl,    (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a).

Another embodiment is the compound described immediately above whereinR³ and R⁵ are further defined as H.

And yet another embodiment is wherein t is further defined as 1 and R¹is selected from: H, halo, (C₁-C₆)alkyl, aryl, heterocyclyl, CN, NH₂, OHand CO₂H.

Also encompassed by the present invention is the compound of Formula Ias further defined immediately above, or a pharmaceutically acceptablesalt or stereoisomer thereof, and wherein R⁴ is selected from:

-   -   1) OC₁-C₆ alkyleneNR⁷R⁸,    -   2) (C═O)_(a)C₀-C₆ alkylene-Q, wherein Q is H, OH, CO₂H, or        OC₁-C₆ alkyl,    -   3) OC₀-C₆ alkylene-heterocyclyl, optionally substituted with one        to three substituents selected from R^(6a),    -   4) C₀-C₆ alkyleneNR⁷R⁸,    -   5) (C═O)NR⁷R⁸, and    -   6) OC₁-C₃ alkylene-(C═O)NR⁷R⁸, and    -   7) SO₂NR⁷R⁸.

Specific example of the compounds of the instant invention include:

-   6-Chloro-3-(1H-indol-2-yl)-21H-indazole-   3-(1H-Indol-2-yl)-1H-indazole-   3-(1H-Indol-2-yl)-1H-indazol-5-ylamine-   3-(1H-Indol-2-yl)-6-methyl-1H-indazole-   3-(1H-Indol-2-yl)4-chloro-1H-indazole-   3-(1H-Indol-2-yl)-7-chloro-1H-indazole-   3-(1H-Indol-2-yl)-4-fluoro-1H-indazole-   3-(1H-Indol-2-yl)-5-fluoro-1H-indazole-   3-(1H-Indol-2-yl)-5-methyl-1H-indazole-   3-(1H-Indol-2-yl)-6-trifluoromethyl-1H-indazole-   3-(1H-Indol-2-yl)-5,6-dimethyl-1H-indazole-   3-(1H-Indol-2-yl)-1H-indazole-6-sulfonic acid amide-   3-(1H-indol-2-yl)-1H-indazole-5-sulfonamide-   3-(1H-Indol-2-yl)-6-bromo-1H-indazole-   3-(1H-Indol-2-yl)-1H-indazole-6-carbonitrile-   3-[5-(piperazin-1-ylsulfonyl)-1H-indol-2-yl]-1H-indazole-   6-(2-Fluoro-pyridin-4-yl)-3(1H-indol-2-yl)-1H-indazole-   4-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H-pyridin-2-one-   3-(1H-Indol-2-yl)-6-(1-oxy-pyridin-3-yl)-1H-indazole-   3-(1H-Indol-2-yl)-6-(1H-pyrrol-2-yl)-1H-indazole-   3-(1H-Indol-2-yl)-6-(1H-pyrrol-3-yl)-1H-indazole-   5-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H-pyridin-2-one-   3-(1H-Indol-2-yl)-6-(1-oxy-pyridin-4-yl)-1H-indazole-   3-(1H-Indol-2-yl)-6-(1H-tetrazol-5-yl)-1H-indazole-   3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}-1H-indazole-   1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]-1-(4-methyl-piperazin-1-yl)-methanone-   1-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-yl]-1-piperazin-1-yl-methanone-   1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]-1-piperazin-1-yl-methanone-   2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide-   Methyl [2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-yl]sulfone-   2-(6-Chloro-1H-indazol-3-yl)-7-fluoro-1H-indole-5-sulfonic acid    amide-   2-(6-Chloro-1H-indazol-3-yl)-6-fluoro-1H-indole-5-sulfonic acid    amide-   2-(6-Chloro-1H-indazol-3-yl)-4-fluoro-1H-indole-5-sulfonic acid    amide-   7-Chloro-2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid    amide-   2-(6-Chloro-5-fluoro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid    amide-   2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-carboxylic acid methyl    ester-   2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-carboxylic acid-   6-Chloro-3-(5-fluoro-1H-indol-2-yl)-1H-indazole-   6-Chloro-3-(5-methyl-1H-indol-2-yl)-1H-indazole-   3-[5-(4-Methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole-   3-[5-(4-Methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole-   6-Chloro-3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole-   6-Chloro-3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole-   1-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-4-methyl-[1,4]diazepan-5-one-   1-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-2-hydroxy-ethanone-   3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-butyric    acid-   6-Chloro-3-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole-   3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-4-ylmethyl]-piperazin-1-yl}-butyric    acid    and the pharmaceutically acceptable salts and optical isomers    thereof.

A preferred embodiment is a compound selected from

-   2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide (5-5)-   6-Chloro-3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole-   1-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-2-hydroxy-ethanone-   3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-butyric    acid-   6-Chloro-3-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole    or a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein may exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof.

When any variable (e.g. R⁴, R⁶, R^(6a), etc.) occurs more than one timein any constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents indicate that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example,“cycloalkyl” inlcudes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“C₂-C₆ alkenyl” means an alkenyl radical having from 2 to 6 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl oracenaphthyl. In cases where the aryl substituent is bicyclic and onering is non-aromatic, it is understood that attachment is via thearomatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo. The term“heterocycle” or “heterocyclyl” as used herein is intended to mean a 5-to 10-membered aromatic or nonaromatic heterocycle containing from 1 to4 heteroatoms selected from the group consisting of O, N and S, andincludes bicyclic groups. “Heterocyclyl” therefore includes the abovementioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

Preferably, heterocycle is selected from 2-azepinone, benzimidazolyl,2-diazapinone, imidazolyl, 2-imidazolidinone, indolyl, isoquinolinyl,morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl,2-piperidinone, 2-pyrimidinone, 2-pyrollidinone, quinolinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.

The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl substituents may be unsubstituted or unsubstituted, unlessspecifically defined otherwise. For example, a (C₁-C₆)alkyl may besubstituted with one, two or three substituents selected from OH, oxo,halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl,piperidinyl, and so on. In this case, if one substituent is oxo and theother is OH, the following are included in the definition:—C═O)CH₂CH(OH)CH₃, —(C═O)OH, —CH₂(OH)CH₂CH(O), and so on.

In certain instances, R⁷ and R⁸ are defined such that they can be takentogether with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said heterocycleoptionally substituted with one or more substituents selected fromR^(6a). Examples of the heterocycles that can thus be formed include,but are not limited to the following, keeping in mind that theheterocycle is optionally substituted with one or more substituentschosen from R^(6a):

Preferably R¹ is selected from: H, halo, (C₁-C₆)alkyl, aryl,heterocyclyl, CN, NH₂, OH and CO₂H.

Also prefered is the definition of R² and R³ as H. Preferably R⁵ is H.

Preferably t is 1 and R⁴ is displaced at the 5-position of the indole,according to the following numbering scheme:

Preferably R⁴ is defined as H, halo, OC₁-C₆ alkyleneNR⁷R⁸,(C═O)_(a)C₀-C₆ alkylene-Q, (wherein Q is H, OH, CO₂H, or OC₁-C₆ alkyl),SO₂NH₂, C₁-C₆ alkyleneNR⁷R⁸ or OC₀-C₆ alkylene-heterocyclyl, optionallysubstituted with one to three substituents selected from R^(6a), C₀-C₆alkyleneNR⁷R⁸, (C═O)NR⁷R⁸, or OC₁-C₃ alkylene-(C═O)NR⁷R⁸. Mostpreferably R⁴ is H or C₁-C₃ alkyleneNR⁷R⁸.

Preferably R⁷ and R⁸ are defined such that they are taken together withthe nitrogen to which they are attached to form a monocyclic 5-7membered heterocycle and optionally containing, in addition to thenitrogen, one or two additional heteroatoms selected from N, O and S,and said heterocycle optionally substituted with one or moresubstituents selected from R^(6a).

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. These schemes, therefore, are not limited bythe compounds listed or by any particular substituents employed forillustrative purposes. Substituent numbering as shown in the schemesdoes not necessarily correlate to that used in the claims.

Schemes

As shown in Scheme A, the indazoline reagent A-2 can be synthesized, bythe general procedures taught by P. M. O'Neill et al. (J. Med. Chem.(1997) 40:437. Derivatives with varying substitution can be made bymodifying this procedure and use of standard synthetic protocols knownin the art. Also shown in Scheme 1 is the preparation of the indoleintermediate A-6 (Tetrahedron 49:49-64 (1993)).

Scheme B illustrates one possible protocol for the coupling of theindole and indazoline intermediates to produce the compounds of theinstant invention. Scheme C illustrates one possible synthetic route tothe synthesis of an indazoline intermediate having a nitrogen atom inthe six-membered ring. The synthesis of a corresponding regioisomer ofthat intermediate is illustrated in Scheme D.

Scheme E illustrates preparation of suitably substituted indoleintermediates that can be used in coupling to the azaindazolineintermediate described in Scheme D. Scheme E also illustratesmanipulation of the indole substituent subsequent to the coupling.

Scheme F illustrates the incorporation of an aryl moiety (optionalllysubstituted) on the indazole ring, via a palladium mediated tincoupling.

Scheme G illustrates an alternative method of forming the indole ring ofthe instant compoundswhich uses an anilinoacetylene as an intermediate(Villemin, D.; Goussu, D.; Heterocycles 1989, 29, 1255).

Scheme H illustrates additional manipulations of the indole substituentsubsequent to the coupling.

Utilities

Utilities

The compounds of the present invention are inhibitors of tyrosine kinaseand are therefore useful to treat or prevent tyrosine kinase-dependentdiseases or conditions in mammals.

“Tyrosine kinase-dependent diseases or conditions” refers to pathologicconditions that depend on the activity of one or more tyrosine kinases.Tyrosine kinases either directly or indirectly participate in the signaltransduction pathways of a variety of cellular activities includingproliferation, adhesion and migration, and differentiation. Diseasesassociated with tyrosine kinase activities include the proliferation oftumor cells, the pathologic neovascularization that supports solid tumorgrowth, ocular neovascularization (diabetic retinopathy, age-relatedmacular degeneration, and the like) and inflammation (psoriasis,rheumatoid artritis, and the like). In treating such conditions with theinstantly claimed compounds, the required therapeutic amount will varyaccording to the specific disease and is readily ascertainable by thoseskilled in the art. Although both treatment and prevention arecontemplated by the scope of the invention, the treatment of theseconditions is the preferred use.

The present invention encompasses a method of treating or preventingcancer in a mammal in need of such treatment which is comprised ofadministering to said mammal a therapeutically effective amount of aclaimed compound. Preferred cancers for treatment are selected fromcancers of the brain, genitourinary tract, lymphatic system, stomach,larynx and lung. Another set of preferred forms of cancer arehistiocytic lymphoma, lung adenocarcinoma, small cell lung cancers,pancreatic cancer, glioblastomas and breast carcinoma. The utility ofangiogenesis inhibitors in the treatment of cancer is known in theliterature, see J. Rak et al. Cancer Research, 55:4575-4580, 1995, forexample. The role of angiogenesis in cancer has been shown in numeroustypes of cancer and tissues: breast carcinoma (G. Gasparini and A. L.harris, J. Clin. Oncol., 1995, 13:765-782; M. Toi et al., Japan. J.Cancer Res., 1994, 85:1045-1049); bladder carcinomas (A. J. Dickinson etal., Br. J. Urol., 1994, 74:762-766); colon carcinomas (L. M. Ellis etal., Surgery, 1996, 120(5):871-878); and oral cavity tumors (J. K.Williams et al., Am. J. Surg., 1994, 168:373-380).

Tumors which have undergone neovascularization show an increasedpotential for metastasis VEGF released from cancer cells enhancesmetastasis possibly by increasing extravasation at points of adhesion tovascular endothelium. (A. Amirkhosravi et al., Platelets, 10:285-292(1999)). In fact, angiogenesis is essential for tumor growth andmetastasis. (S. P. Cunningham, et al., Can. Research, 61: 3206-3211(2001)). The angiogenesis inhibitors disclosed in the presentapplication are therefore also useful to prevent or decrease tumor cellmetastasis. Such a use is also contemplated to be within the scope ofthe present invention.

Further included within the scope of the invention is a method oftreating or preventing a disease in which angiogenesis is implicated,which is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention. Ocular neovascular diseases are an example ofconditions where much of the resulting tissue damage can be attributedto aberrant infiltration of blood vessels in the eye (see WO 00/30651,published 2 Jun. 2000). The undesireable infiltration can be triggeredby ischemic retinopathy, such as that resulting from diabeticretinopathy, retinopathy of prematurity, retinal vein occlusions, etc.,or by degenerative diseases, such as the choroidal neovascularizationobeserved in age-related macular degeneration. Inhibiting the growth ofblood vessels by administration of the present compounds would thereforeprevent the infiltration of blood vessels and prevent or treat diseaseswhere angiogenesis is implicated, such as ocular diseases like retinalvascularization, diabetic retinopathy, age-related macular degeneration,and the like.

Also included within the scope of the present invention is a method oftreating or preventing inflammatory diseases which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of Formual I. Examples of suchinflammatory diseases are rheumatoid arthritis, psoriasis, contactdermatitis, delayed hypersensitivity reactions, and the like. (A.Giatromanolaki et al., J. Pathol. 2001; 194:101-108.) For the role ofVEGF in skin angiogenesis, see Michael Detmar, J. Dermatological Sci.,24 Suppl. 1, S78-S84 (2000).

Also included within the scope of the present invention is a method oftreating or preventing bone associated pathologies selected fromosteosarcoma, osteoarthritis, and rickets, also known as oncogenicosteomalacia. (Hasegawa et al., Skeletal Radiol., 28, pp.41-45, 1999;Gerber et al., Nature Medicine, Vol. 5, No. 6, pp.623-628, June 1999.)And since VEGF directly promotes osteoclastic bone resorption throughKDR/Flk-1 expressed in mature osteoclasts (FEBS Let. 473:161-164 (2000);Endocrinology, 141:1667 (2000)), the instant compounds are also usefulto treat and prevent conditions related to bone resorption, such asosteoporosis and Paget's disease.

A method of treating or preventing preeclampsia is also within the whichcomprises administering a therapeutically effective amount of a compoundof the present invention. Studies have shown that the action of VEGF onthe Flt-1 receptor is pivotal in the pathogenesis of preeclampsia.(Laboratory Investigation 79:1101-1111 (September 1999).) Vessels ofpregnant women incubated with VEGF exhibit a reduction inendothelium-dependent relaxation similar to that induced by plasma fromwomen with preeclampsia. In the presence of an anti-Flt-1 receptorantibody, however, neither VEGF or plasma from women with preeclampsiareduced the. endothelium-dependent relaxation. Therefore the claimedcompounds serve to treat preeclampsia via their action on the tyrosinekinase domain of the Flt-1 receptor.

Also within the scope of the invention is a method of reducing orpreventing tissue damage following a cerebral ischemic event whichcomprises administering a therapeutically effective amount of a compoundof the present invention. The claimed compounds can also be used toreduce or prevent tissue damage which occurs after cerebral ischemicevents, such as stroke, by reducing cerebral edema, tissue damage, andreperfusion injury following ischemia. (Drug News Perspect 11:265-270(1998); J. Clin. Invest. 104:1613-1620 (1999); Nature Med 7:222-227(2001)).

The instant compounds can also be used to prevent or treat tissue damageduring bacterial meningitis, such as tuberculous meningitis. Matsuyamaet al., J. Neurol. Sci. 186:75-79 (2001)). The instant inventiontherefore encompasses a method of treating or preventing tissue damagedue to bacterial meningitis which comprises administering atherapeutically effective amount of a claimed compound. Studies haveshown that VEGF is secreted by inflammatory cells during bacterialmeningitis and that VEGF contributes to blood-brain barrier disruption.(van der Flier et al., J. Infectious Diseases, 183:149-153 (2001)). Theclaimed compounds can inhibit VEGF-induced vascular permeability andtherefore serve to prevent or treat blood-brain barrier disruptionassociated with bacterial meningitis.

The present invention further encompasses a method to treat or preventendometrioses comprised of administering a therapeutically effectiveamount of a claimed compound. An increase in VEGF expression andangiogenesis is associated with the progression of endometriosis(Stephen K. Smith, Trends in Endocrinology &Metabolism, Vol. 12, No. 4,May/June 2001). Inhibition of VEGF by the current compounds wouldtherefore inhibit angiogenesis and treat endometriosis.

A further embodiment of the present invention is a method of treatingacute myeloid leukemia (AML) which comprises administering atherapeutically effective amount of a claimed compound. Activation ofFLT3 on leukemic cells by FLT3 ligand leads to receptor dimerization andsignal transduction in pathways that promote cell growth and inhibitapoptosis (Blood, Vol. 98, No. 3, pp.885-887 (2001)). The presentcompounds are therefore useful to treat AML via inhibition of thetyrosine kinase domain of Flt-3.

The instant compounds can also be used to prevent or treat tissue damageduring bacterial meningitis, such as tuberculous meningitis. Matsuyamaet al., J. Neurol Sci. 186:75-79 (2001)). The instant inventiontherefore encompasses a method of treating or preventing tissue damagedue to bacterial meningitis which comprises administering atherapeutically effective amount of a compound of Formula 1. Studieshave shown that VEGF is secreted by inflammatory cells during bacterialmeningitis and that VEGF contributes to blood-brain barrier disruption.(van der Flier et al., J. Infectious Diseases, 183:149-153 (2001)). Theclaimed compounds can inhibit VEGF-induced vascular permeability andtherefore serve to prevent or treat blood-brain barrier disruptionassociated with bacterial meningitis.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The instant compounds are also useful in combination with knowntherapeutic agents and anti-cancer agents, as described in U.S. Pat. No.6,245,759 B1 (columns 14-19) and PCT Publ. No. WO 01/29025 (pages 33-41)(both of which are incorporated by reference).

The instant compounds are also useful in combination with knownanti-cancer agents. Such known anti-cancer agents include the following:estrogen receptor modulators, androgen receptor modulators, retinoidreceptor modulators, cytotoxic agents, antiproliferative agents,prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIVprotease inhibitors, reverse transcriptase inhibitors, and otherangiogenesis inhibitors. The instant compounds are particularly usefulwhen coadminsitered with radiation therapy. The synergistic effects ofinhibiting VEGF in combination with radiation therapy have beendescribed in the art (see WO 00/61186).

“Estrogen receptor modulators” refers to compounds which interfere orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic agents” refer to compounds which cause cell death primarilyby interfering directly with the cell's functioning or inhibit orinterfere with cell myosis, including alkylating agents, tumor necrosisfactors, intercalators, microtubulin inhibitors, and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride,diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, ME10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine, (5a, 5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl) urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-flurouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also includes monoclonal antibodies to. growth factors, otherthan those listed under “angiogenesis inhibitors”, such as trastuzumab,and tumor suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for HMG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938;4,294,926; 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos.4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat.Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772; 4,911,165;4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), atorvastatin(LIPITOR®; see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691;5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

In HMG-CoA reductase inhibitors where an open-acid form can exist, saltand ester forms may preferably be formed from the open-acid, and allsuch forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin. Herein, the term “pharmaceutically acceptablesalts” with respect to the HMG-COA reductase inhibitor shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, and tris(hydroxymethyl) aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compoundsmay act as prodrugs which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase). Examples of prenyl-protein transferase inhibiting compoundsinclude(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)quinolinone,(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl)-2-piperazinone,5(S)-n-Butyl-1-(2-methylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone,1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine,4-{5-[4-hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(5-chloro-2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-{3-[4-(2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl}benzonitrile,18,19-dihydro-19-oxo-5H,17H-6,10:12,16-dimetheno-1H-imidazo[4,3-c][1,11,4]dioxaazacyclo-nonadecine-9-carbonitrile,(±)-19,20-dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile,19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6,10:12,16-dimetheno-22H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile,and(±)-19,20-dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.

Other examples of prenyl-protein transferase inhibitors can be found inthe following publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer, Vol. 35, No. 9, pp.1394-1401 (1999).

Examples of HIV protease inhibitors include amprenavir, abacavir,CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir,ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632. Examples ofreverse transcriptase inhibitors include delaviridine, efavirenz,GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddI.

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR20), inhibitors of epidermal-derived,fibroblast-derived, or platelet derived growth factors, MMP (matrixmetalloprotease) inhibitors, integrin blockers, interferon-α,interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors,including nonsteroidal anti-inflammatories (NSAIDs) like aspirin andibuprofen as well as selective cyclooxygenase-2 inhibitors likecelecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69,p. 475 (1982); Arch. Opthalmol., Vol. 108, p.573 (1990); Anat. Rec.,Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin,Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16,p.107.(1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res.,Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol.,Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)),carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab.Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see; NatureBiotechnology, Vol. 17, pp.963 968 (October 1999); Kim et al., Nature,362, 841-844 (1993); WO 00/44777; and WO 00/61186).

As described above, the combinations with NSAID's are directed to theuse of NSAID's which are potent COX-2 inhibiting agents. For purposes ofthis specification an NSAID is potent if it possess an IC₅₀ for theinhibition of COX-2 of 1 μM or less as measured by the cell ormicrosomal assay disclosed herein.

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by the cell or micromsal assay disclosed hereinunder. Suchcompounds include, but are not limited to those disclosed in U.S. Pat.No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issuedJan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat.No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr.25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No.5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, U.S. Pat. No. 5,710,140, issued Jan.20,1998, WO 94/15932, published Jul. 21, 1994, U.S. Pat. No. 5,344,991,issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S.Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790,issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995,U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No.5,932,598, issued Aug. 3, 1999, all of which are hereby incorporated byreference.

Other examples of specific inhibitors of COX-2 include the following:

-   3-(3-fluorophenyl)-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanone;-   3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;-   3-(3,4-dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;-   3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;-   5,5-dimethyl-3-(3-fluorophenyl)-4-(methylsulfonyl)phenyl)-2-(5H)-furanone;-   3-(4-methylsulfonyl)phenyl-2-phenyl-5-trifluoromethylpyridine;-   2-(3-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine;-   2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine;-   2-(4-fluorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine;-   3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)-5-trifluoromethylpyridine;-   5-methyl-3-(4-methylsulfonyl)phenyl-2-phenylpyridine;-   2-(4-chlorophenyl)-5-methyl-3-(4-methylsulfonyl) phenylpyridine;-   5-methyl-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine;-   5-chloro-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-pyridinyl) pyridine;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(4-pyridinyl) pyridine;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine;-   2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic    acid methyl ester;-   2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic    acid;-   5-cyano-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine    hydromethanesulfonate;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine    hydrochloride;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine    hydrochloride;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine;-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(2ethyl-5-pyridinyl)pyridine    hydromethanesulfonate;-   3-(3,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(3-fluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(3,5-difluorophenoxy)-5,5-dimethyl-4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-phenoxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(2,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(4-chlorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(3,4-dichlorophenoxy)-5,5-dimethyl-4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(4-fluorophenoxy)-5,5-dimethyl-41-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(4-fluorophenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(3,5-difluorophenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-phenylthio-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(N-phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(N-methyl-N-phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-cyclohexyloxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-phenylthio-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-benzyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(3,4-difluorophenylhydroxymethyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(3,4-difluorobenzoyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-benzoyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-oxaspiro[4.4]non-3-en-2-one;-   4-(4-(methylsulfonyl)phenyl)-3-phenylthio-1-oxaspiro[4.4]non-3-en-2-one;-   4-(2-oxo-3-phenylthio-1-oxa-spiro[4,4]non-3-en-4-yl)    benzenesulfonamide;-   3-(4-fluorobenzyl)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(3,4-difluorophenoxy)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(5-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(3-isoquinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(4-(methylsulfonyl)phenyl)-2-phenoxycyclopent-2-enone;-   3-(4-(methylsulfonyl)phenyl)-2-(3,4-fluorophenoxy)cyclopent-2-enone;-   5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(5-bromopyridin-2-yloxy)-5H-furan-2-one;-   5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-one;-   2-(3,4-difluorophenoxy)-3-(4-methylsulfonylphenyl)cyclopent-2-enone;-   3-(5-benzothiophenyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   5,5-dimethyl-4-(4methylsulfonyl-phenyl)-3-(pyridyl-4-oxy)-5H-furan-2-one;-   5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(pyridyl-3-oxy)-5H-furan-2-one;-   3-(2-methyl-5-pyridyloxy)-5,5-dimethyl(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(2-fluoro-4-trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;-   3-(5-chloro-2-pyridylthio)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   2-(3,5-difluorophenoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enone;-   3-(2-pyrimidinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(3-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(3-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(3-(1,2,5-thiadiazolyl)oxy)-4-(4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;-   3-(5-isoquinolinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(6-amino-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(3-chloro-4-fluoro)phenoxy-4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;-   3-(6-quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(2-thiazolylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(3-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-one;-   3-(3-trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one;-   5,5-dimethyl-(4-(4-methylsulfonyl)phenyl)-3-(piperidine-1-carbonyl)-5-H-furan-2-one;-   5,5-dimethyl-3-(2-Butoxy)-4-(4-methylsulfonylphenyl)-5H-furan-2-one;-   5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(3-pentoxy)-5H-furan-2-one;-   2-(5-chloro-2-pyridyloxy)-3-(4-methylsulfonyl)phenylcyclopent-2-enone;-   3-(4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(3,4-difluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-chlorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(2-methyl-3-pyridyloxy)-5    ,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(4-methyl-5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(5-chloro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(5-fluoro-4methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(3-chloro-2-pyridyloxy)-5;5-dimethyl-4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-propyl-5H-furan-2-one;-   3-(N,N-diethylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(3,5-dichloro-2-pyridyloxy)-5H-furan-2-one;-   (5R)-3-(4-bromophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-methoxyphenoxy)-5yl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(5-chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;-   3-(5-chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-propyl-5H-furan-2-one;-   3-(1-cyclopropyl-ethoxy)-5,5-dimethyl-4-(4-methyl    sulfonyl)phenyl)-5H-furan-2-one;-   5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-(propoxy)-5-(2-trifluoroethyl)-5H-furan-2-one;-   5(R)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one;-   5,5-dimethyl-3-(2,2-dimethylpropyloxy)-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   5(R)-3-(1-cyclopropyl-ethoxy)-5-ethyl-5-methyl-4-(4-(methyl    sulfonyl)phenyl-5H-furan-2-one;-   5(S)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl-3-(2-propoxy)-5H-furan-2-one;-   3-(1-cyclopropyl-ethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   5,5-dimethyl-3-(isobutoxy)-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(4-bromophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(2-quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(2-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(6-benzothiazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(6-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)    phenyl)-5H-furan-2-one;-   3-(4-quinazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   (5R)-3-(5-fluoro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(5-fluoro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;-   3-(1-isoquinolinyloxy)-5,5-dimethyl-4-(methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;-   3-(3-fluoro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)    phenyl-5H-furan-2-one;-   (5R)-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)    phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;-   (5R)-3-(5-chloro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(3,4-difluorophenoxy)-5-methyl-5-trifluoromethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(3,4-difluorophenoxy)-5-methyl-4-(4-(methylsulfonyl)phenyl)-5-propyl-5H-furan-2-one;-   3-cyclobutyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl-5H-furan-2-one;-   3-(1-indanyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;-   3-(2-indanyloxy)-5,5-dimethyl-(4-methylsulfonyl)phenyl)-5H-furan-2-one;-   3-cyclopentyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)5H-furan-2-one;-   3-(3,3-dimethylcyclopentyloxy)-5    ,5-dimethyl-4-(4-methylsulfonyl-phenyl)-5H-furan-2-one;-   3-isopropoxy-5-methyl-4-(4-methylsulfonylphenyl)-5-propyl-5H-furan-2-one;-   3-(2-methoxy-5-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(5-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5RS)-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;-   3-(3-chloro-4-methoxyphenoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(3-chloro-4-methoxyphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-chlorophenoxy)-5-trifluoroethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-bromophenoxy)-5-trifluoroethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   5-cyclopropylmethyl-3-(3,4-difluorophenoxy)-5-methyl-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(3-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-chloro-3-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-phenoxy-5-ethyl-5-methyl-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(4-chloro-3-methylphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(4-chloro-3-methylphenoxy)-5-5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   (5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;-   (5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-ethyl-5-methyl-5H-furan-2-one;-   3-(5-chloro-6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(5-cyclopropyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;-   3-(1-cyclopropylethoxy)-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;    and-   3-(cyclopropylmethoxy)-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;    or a pharmaceutically acceptable salt or stereoisomer thereof.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are:

-   3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and-   5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine;    or a pharmaceutically acceptable salt thereof.

General and specific synthetic procedures for the preparation of theCOX-2 inhibitor compounds described above are found in U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, and U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, all ofwhich are herein incorporated by reference.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to, the following:

or a pharmaceutically acceptable salt thereof.

Compounds which are described as specific inhibitors of COX-2 and aretherefore useful in the present invention, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference: WO 94/15932,published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994,U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738,issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995,U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999.

Compounds which are specific inhibitors of COX-2 and are thereforeuseful in the present invention, and methods of synthesis thereof, canbe found in the following patents, pending applications andpublications, which are herein incorporated by reference: U.S. Pat. No.5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan.19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No.6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr. 25,1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No.5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug.27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No.5,698,584, issued Dec. 16, 1997, and U.S. Pat. No. 5,710,140, issuedJan. 20,1998.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostation, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101,squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaosephosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonyl-imino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the α_(v)β₅ integrin,to compounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and (α₆β₄ integrins. The term alsorefers to antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, STI571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

The instant compounds are also useful, alone or in combination withplatelet fibrinogen receptor (GP IIb/IIIa) antagonists, such astirofiban, to inhibit metastasis of cancerous cells. Tumor cells canactivate platelets largely via thrombin generation. This activation isassociated with the release of VEGF. The release of VEGF enhancesmetastasis by increasing extravasation at points of adhesion to vascularendothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, thepresent compounds can serve to inhibit metastasis, alone or incombination with GP IIb/IIIa) antagonists. Examples of other fibrinogenreceptor antagonists include abciximab, eptifibatide, sibrafiban,lamifiban, lotrafiban, cromofiban, and CT50352.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's bloodstream by local bolus injection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The scope of the invetion therefore encompasses the use of the instantlyclaimed compounds in combination with a second compound selected from:

-   -   1) an estrogen receptor modulator,    -   2) an androgen receptor modulator,    -   3) retinoid receptor modulator,    -   4) a cytotoxic agent,    -   5) an antiproliferative agent,    -   6) a prenyl-protein transferase inhibitor,    -   7) an HMG-CoA reductase inhibitor,    -   8) an HIV protease inhibitor,    -   9) a reverse transcriptase inhibitor, and    -   10) another angiogenesis inhibitor.

Preferred angiogenesis inhibitors to be useed as the second compound area tyrosine kinase inhibitor, an inhibitor of epidermal-derived growthfactor, an inhibitor of fibroblast-derived growth factor, an inhibitorof platelet derived growth factor, an MMP (matrix metalloprotease)inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosanpolysulfate, a cyclooxygenase inhibitor, carboxyamido-triazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, or an antibody to VEGF. Preferredestrogen receptor modulators are tamoxifen and raloxifene.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of Formula I in combination with radiation therapy and/or incombination with a compound selected from:

-   -   1) an estrogen receptor modulator,    -   2) an androgen receptor modulator,    -   3) retinoid receptor modulator,    -   4) a cytotoxic agent,    -   5) an antiproliferative agent,    -   6) a prenyl-protein transferase inhibitor,    -   7) an HMG-CoA reductase inhibitor,    -   8) an MV protease inhibitor,    -   9) a reverse transcriptase inhibitor, and    -   10) another angiogenesis inhibitor.

And yet another embodiment of the invention is a method of treatingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with paclitaxel ortrastuzumab.

The invention further encompasses a method of treating or preventingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with a COX-2 inhibitor.

These and other aspects of the invention will be apparent from theteachings contained herein.

Assays

The compounds of the instant invention described in the Examples weretested by the assays described below and were found to have kinaseinhibitory activity. Other assays are known in the literature and couldbe readily performed by those of skill in the art (see, for example,Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk etal., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst.52:413-427; Nicosia et al., In Vitro 18:538-549).

I. VEGF Receptor Kinase Assay

VEGF receptor kinase activity is measured by incorporation ofradio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY)substrate. The phosphorylated pEY product is trapped onto a filtermembrane and the incorporation of radio-labeled phosphate quantified byscintillation counting.

Materials

VEGF Receptor Kinase

The intracellular tyrosine kinase domains of human KDR (Terman, B. I. etal. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. etal. Oncogene (1990) vol. 5, pp. 519-524) were cloned as glutathioneS-transferase (GST) gene fusion proteins. This was accomplished bycloning the cytoplasmic domain of the KDR kinase as an in frame fusionat the carboxy terminus of the GST gene. Soluble recombinant GST-kinasedomain fusion proteins were expressed in Spodoptera frugiperda (Sf21)insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T,Pharmingen).

The other materials used and their compositions were as follows:

-   Lysis buffer: 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA,    0.5% triton X-100, 10% glycerol, 10 mg/mL of each leupeptin,    pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride (all    Sigma).-   Wash buffer: 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA,    0.05% triton X-100, 10% glycerol, 10 mg/mL of each leupeptin,    pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.-   Dialysis buffer: 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA,    0.05% triton X-100, 50% glycerol, 10 mg/mL of each leupeptin,    pepstatin and aprotinin and 1 mM phenylmethylsuflonyl fluoride.-   10× reaction buffer: 200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl₂,    10 mM DTT and 5 mg/mL bovine serum albumin (Sigma).-   Enzyme dilution buffer: 50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT,    10% glycerol, 100 mg/mL BSA.-   10× Substrate: 750 μg/mL poly (glutamic acid, tyrosine; 4:1)    (Sigma).-   Stop solution: 30% trichloroacetic acid, 0.2 M sodium pyrophosphate    (both Fisher).-   Wash solution: 15% trichloroacetic acid, 0.2 M sodium pyrophosphate.-   Filter plates: Millipore #MAFC NOB, GF/C glass fiber 96 well plate.

Method

A. Protein Purification

1. Sf21 cells were infected with recombinant virus at a multiplicity ofinfection of 5 virus particles/cell and grown at 27° C. for 48 hours.

2. All steps were performed at 4° C. Infected cells were harvested bycentrifugation at 1000×g and lysed at 4° C. for 30 minutes with{fraction (1/10)} volume of lysis buffer followed by centrifugation at100,000×g for 1 hour. The supernatant was then passed over a glutathioneSepharose column (Pharmacia) equilibrated in lysis buffer and washedwith 5 volumes of the same buffer followed by 5 volumes of wash buffer.Recombinant GST-KDR protein was eluted with wash buffer/10 mM reducedglutathione (Sigma) and dialyzed against dialysis buffer.

B. VEGF Receptor Kinase Assay

1. Add 5 μl of inhibitor or control to the assay in 50% DMSO.

2. Add 35 μl of reaction mix containing 5 μl of 10× reaction buffer, 5μl 25 mM ATP/10 μCi [³³P]ATP (Amersham), and 5 μl 10× substrate.

3. Start the reaction by the addition of 10 μl of KDR (25 nM) in enzymedilution buffer.

4. Mix and incubate at room temperature for 15 minutes.

5. Stop by the addition of 50 μl stop solution.

6. Incubate for 15 minutes at 4° C.

7. Transfer a 90 μl aliquot to filter plate.

8. Aspirate and wash 3 times with wash solution.

9. Add 30 μl of scintillation cocktail, seal plate and count in a WallacMicrobeta scintillation counter.

II. Human Umbilical Vein Endothelial Cell Mitogenesis Assay

Human umbilical vein endothelial cells (HUVECs) in culture proliferatein response to VEGF treatment and can be used as an assay system toquantify the effects of KDR kinase inhibitors on VEGF stimulation. Inthe assay described, quiescent HUVEC monolayers are treated with vehicleor test compound 2 hours prior to addition of VEGF or basic fibroblastgrowth factor (bFGF). The mitogenic response to VEGF or bFGF isdetermined by measuring the incorporation of [³H]thymidine into cellularDNA.

Materials

-   HUVECs: HUVECs frozen as primary culture isolates are obtained from    Clonetics Corp. Cells are maintained in Endothelial Growth Medium    (EGM; Clonetics) and are used for mitogenic assays described in    passages 3-7 below.-   Culture Plates: NUNCLON 96-well polystyrene tissue culture plates    (NUNC #167008).-   Assay Medium: Dulbecco's modification of Eagle's medium containing 1    g/mL glucose (low-glucose DMEM; Mediatech) plus 10% (v/v) fetal    bovine serum (Clonetics).-   Test Compounds: Working stocks of test compounds are diluted    serially in 100% dimethylsulfoxide (DMSO) to 400-fold greater than    their desired final concentrations. Final dilutions to 1×    concentration are made directly into Assay Medium immediately prior    to addition to cells.-   10× Growth Factors: Solutions of human VEGF₁₆₅ (500 ng/mL; R&D    Systems) and bFGF (10 ng/mL; R&D Systems) are prepared in Assay    Medium.-   10× [³H]Thymidine: [Methyl-³H]thymidine (20 Ci/mmol; Dupont-NEN) is    diluted to 80 μCi/mL in low-glucose DMEM.-   Cell Wash Medium: Hank's balanced salt solution (Mediatech)    containing 1 mg/mL bovine serum albumin (Boehringer-Mannheim).-   Cell Lysis Solution: 1 N NaOH, 2% (w/v) Na₂CO₃.

Method

1. HUVEC monolayers maintained in EGM are harvested by trypsinizationand plated at a density of 4000 cells per 100 μL Assay Medium per wellin 96-well plates. Cells are growth-arrested for 24 hours at 37° C. in ahumidified atmosphere containing 5% CO₂.

2. Growth-arrest medium is replaced by 100 μL Assay Medium containingeither vehicle (0.25% [v/v] DMSO) or the desired final concentration oftest compound. All determinations are performed in triplicate. Cells arethen incubated at 37° C. with 5% CO₂ for 2 hours to allow test compoundsto enter cells.

3. After the 2-hour pretreatment period, cells are stimulated byaddition of 10 μL/well of either Assay Medium, 10× VEGF solution or 10×bFGF solution. Cells are then incubated at 37° C. and 5% CO₂.

4. After 24 hours in the presence of growth factors, 10× [³H]thymidine(10 μL/well) is added.

5. Three days after addition of [³H]thymidine, medium is removed byaspiration, and cells are washed twice with Cell Wash Medium (400μL/well followed by 200 μL/well). The washed, adherent cells are thensolubilized by addition of Cell Lysis Solution (100 μL/well) and warmingto 37° C. for 30 minutes. Cell lysates are transferred to 7-mL glassscintillation vials containing 150 μL of water. Scintillation cocktail(5 mL/vial) is added, and cell-associated radioactivity is determined byliquid scintillation spectroscopy.

Based upon the foregoing assays the compounds of the present inventionare inhibitors of VEGF and thus are useful for the inhibition ofangiogenesis, such as in the treatment of ocular disease, e.g., diabeticretinopathy and in the treatment of cancers, e.g., solid tumors. Theinstant compounds inhibit VEGF-stimulated mitogenesis of human vascularendothelial cells in culture with IC₅₀ values between 0.01-5.0 μM. Thesecompounds may also show selectivity over related tyrosine kinases (e.g.,FGFR1 and the Src family; for relationship between Src kinases and VEGFRkinases, see Eliceiri et al., Molecular Cell, Vol. 4, pp.915-924,December 1999).

III. FLT-1 Kinase Assay

Flt-1 was expressed as a GST fusion to the Flt-1 kinase domain and wasexpressed in baculovirus/insect cells. The following protocol wasemployed to assay compounds for Flt-1 kinase inhibitory activity:

-   1. Inhibitors were diluted to account for the final dilution in the    assay, 1:20.-   2. The appropriate amount of reaction mix was prepared at room    temperature:    -   10× Buffer (20 mM Tris pH 7.4/0.1 M NaCl/1 mM DTT final)    -   0.1M MnCl₂ (5 mM final)    -   pEY substrate (75 μg/mL)    -   ATP/[³³P]ATP (2.5 μM/1 μCi final)    -   BSA (500 μg/mL final).-   3. 5 μL of the diluted inhibitor was added to the reaction mix.    (Final volume of 5 μL in 50% DMSO). To the positive control wells,    blank DMSO (50%) was added.-   4. 35 μL of the reaction mix was added to each well of a 96 well    plate.-   5. Enzyme was diluted into enzyme dilution buffer (kept at 4° C.).-   6. 10 μL of the diluted enzyme was added to each well and mix (5 nM    final).

To the negative control wells, 10 μL 0.5 M EDTA was added per wellinstead (final 100 mM).

-   7. Incubation was then carried out at room temperature for 30    minutes.-   8. Stopped by the addition of an equal volume (50 μL) of 30%    TCA/0.1M Na pyrophosphate.-   9. Incubation was then carried out for 15 minutes to allow    precipitation.-   10. Transfered to Millipore filter plate.-   11. Washed 3× with 15% TCA/0.1M Na pyrophosphate (125 μL per wash).-   12. Allowed to dry under vacuum for 2-3 minutes.-   13. Dryed in hood for ˜20 minutes.-   14. Assembled Wallac Millipore adapter and added 50 μL of    scintillant to each well and counted.    IV. FLT-3 Kinase Assay

Flt-3 was expressed as a GST fusion to the Flt-3 kinase domain, and wasexpressed in baculovirus/insect cells. The following protocol wasemployed to assay compounds for Flt-3 kinase inhibitory activity:

-   1. Dilute inhibitors (account for the final dilution into the assay,    1:20)-   2. Prepare the appropriate amount of reaction mix at room    temperature.    -   10× Buffer (20 mM Tris pH 7.4/0.1 M NaCl/1 mM DTT final)    -   0.1M MnCl₂ (5 mM final)    -   pEY substrate (75 μg/mL)    -   ATP/[³³P]ATP (0.5 μM/L μCi final)    -   BSA (500 μg/mL final)-   3. Add 5 μL of the diluted inhibitor to the reaction mix. (Final    volume of 5 μL in 50% DMSO). Positive control wells—add blank DMSO    (50%).-   4. Add 35 μL of the reaction mix to each well of a 96 well plate.-   5. Dilute enzyme into enzyme dilution buffer (keep at 4° C.).-   6. Add 10 μL of the diluted enzyme to each well and mix (5-10 nM    final).

Negative control wells—add 10 μL 0.5 M EDTA per well instead (final 100mM)

-   7. Incubate at room temperature for 60 min.-   8. Stop by the addition of an equal volume (50 μL) of 30% TCA/0.1M    Na pyrophosphate.-   9. Incubate for 15 min to allow precipitation.-   10. Transfer to Millipore filter plate.-   11. Wash 3× with 15% TCA/0.1M Na pyrophosphate (125 μL per wash).-   12. Allow to dry under vacuum for 2-3 min.-   13. Dry in hood for ˜20 min.-   14. Assemble Wallac Millipore adapter and add 50 μL of scintillant    to each well and count.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be illustrative of the invention and not limiting of thereasonable scope thereof.

Example 1

Step 1: 6-chloroindazole (1-3b)

A slurry of 5-chloro-2-methylaniline (1-1, 30 g, 0.21 mol) in water (200mL) was treated with HCl (12N, 53 mL, 0.64 mol). The resulting solutionwas cooled to 0° C. and reacted with aqueous solution of sodium nitrite(14.6 g, 0.21 mol). After 30 min. stirring, any insoluble particles wereremoved by filtration and the filtrate solution was treated at 0° C.with sodium tetrafluoroborate dissolved in water (150 mL). Precipitatesso formed was collected by filtration, washed with ice-cold water, coldmethanol and then with ethylether. The product (1-2) was dried in vacuoand then suspended in chloroform (500 mL) in the presence of potassiumacetate (34 g, 0.35 mol) and 18-crown-6 (2.29 g, 8.67 mmol). Thereaction mixture was stirred at the ambient temperature for 1.5 h,partitioned between ethyl acetate and water. The organic layer waswashed with brine, separated, dried (MgSO₄) and concentrated in vacuo.Trituation with dichloromethane and hexanes afforded the desired productas an orange powder (1-3); ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (bs, 1 H),8.11 (s, 1 H), 7.79 (d, 1 H, J=8.7 Hz), 7.62 (s, 1 H), 7.13 (dd, 1 H,J=7.9, 1.9 Hz).

Step 2: 6-chloro-3-iodoindazole (1-4)

A solution of 6-chloroindazole (1-3, 5.24 g, 34.3 mmol) in ethanol (500mL) was reacted at the ambient temperature with iodine (8.72 g, 34.3mmol) in the presence of silver sulfate (10.7 g, 34.3 mmol). After 2 hstirring at the same temperature, all the precipitates were removed byfiltration and the filtrate solution was concentrated in vacuo.Trituation with dichloromethane and hexanes gave the desired product asan orange solid (1-4); ¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (bs, 1 H), 7.66(d, 1 H, J=1.6 Hz), 7.46 (d, 1 H, J=8.5 Hz), 7.21 (dd, 1 H, J=8.6, 1.6Hz).

Step 3: N-tert-butyloxycarbonylindole-2-boronic Acid (1-5)

A stirred solution of indole (8.2 g; 70 mmol) in CH₂Cl₂ (200 mL) wasreacted with di-tert-butyl dicarbonate (18.3 g; 84 mmol) in the presenceof N,N-dimethylaminopyridine (430 mg; 3.5 mmol). The reaction mixturewas stirred overnight, concentrated in vacuo. The resulting crudeproduct was diluted with tetrahydrofuran (200 mL), cooled to −78° C. andtreated with 3M-lithuim diisopropylamide (35 mL; 105 mmol). After 2 hstirring at the same temperature, the reaction mixture was quenched withtrimethylborate (23.8 mL; 210 mmol), warmed to room temperature andpartitioned between ethyl acetate and 0.3N-HCl. The organic layer waswashed with brine, separated, dried (MgSO₄) and concentrated in vacuo.Trituation of the solid with hexanes and filtration afforded the desiredproduct as a pale tan solid (1-5); ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (bs,2H), 8.07 (d, 1H, J=8.1 Hz), 7.54 (d, 1H, J=7.5 Hz), 7.26 (t, 1H, J=7.5Hz), 7.17 (t, 1H, J=7.8 Hz), 6.61 (s, 1H), 1.59 (s, 9H).

Step 4: 6-Chloro-3-(1H-indol-2-yl)-1H-indazole (1-7)

A biphasic reaction mixture of the iodide (1-4, 1.2 g, 4.31 mmol), theboronic acid (1-5, 1.35 g, 5.17 mmol),tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol), lithiumchloride (548 mg, 12.9 mmol), and Na₂CO₃ (2M, 3 mL) in dioxane (9 mL)was heated at 70° C. for 2 h under the nitrogen atmosphere. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, separated, dried (MgSO₄) and concentratedin vacuo. Chromatography (SiO₂, 33% ethyl acetate in hexanes) followedby concentration afforded 1-6 as a pale brown solid. The intermediate,1-6, was dissolved in dichloromethane (6 mL) and treated at the ambienttemperature with trifluoroacetic acid (6 mL) in the presence of dimethylsulfide (0.05 mL) and water (0.05 mL). After 3 h stirring, the reactionmixture was concentrated in vacuo and partitioned between ethyl acetateand saturated aqueous sodium bicarbonate solution. The organic layer wasseparated, dried (MgSO₄), and concentrated in vacuo. Chromatography(SiO₂, 33% ethyl acetate in hexanes) followed by concentration afforded1-7 as a pale brown solid.; ¹H NMR (400 MHz, CDCl₃) δ 10.34 (bs, 1H),9.73 (bs, 1H), 8.15 (d, 1H, J=7.9 Hz), 7.71 (d, 1H, J=7.8 Hz), 7.66 (d,1 H, J=1.6 Hz), 7.46 (d, 1 H, J=8.5 Hz), 7.30 (t, 1H, J=7.5 Hz), 7.21(dd, 1 H, J=8.6, 1.6 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.16 (s, 1H).

3-(1H-Indol-2-yl)-1H-indazole (1-8)

Compound 1-8 was prepared by the same chemical transformations shown inScheme 1 (1-3 to 1-7), but substituting 2-methylaniline for the 2-methyl5-chloroaniline in Step 1; ¹H NMR (400 MHz, CDCl₃) δ 10.17 (bs, 1H),9.22 (bs, 1H), 8.15 (d, 1H, J=7.9 Hz), 7.71 (d, 1H, J=7.8 Hz), 7.50 (t,1H, J=7.7 Hz), 7.46 (t, 1H, J=7.8 Hz), 7.42 (d, 1H, J=7.7 Hz), 7.30 (t,1H, J=7.5 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.16 (s, 1H), 7.14 (d, 1H, J=7.7Hz).

Compounds in Table 1 were prepared as shown in Scheme 1, butsubstituting the appropriate substituted 2-methylaniline for the5-chloro-2-methylaniline in Step 1: TABLE 1 # Structure Nomenclature andSpectral Data 1-9

3-(1H-Indol-2-yl)-1H-indazol-5-ylamine ¹H NMR(400 MHz, DMSO-d₆)δ13.27(s, 1H), 12.34(s, 1H), 8.24(d, 1H, J=7.8Hz), 7.76(s, 1H), 7.63(d,1H, J=7.6Hz), 7.42(d, 1H, J=8.5 Hz), 7.33(t, 1H, J=7.8Hz), 7.25(t, 1H,J=7.7 Hz), 6.70(s, 1H), 6.39(d, 1H, J=8.6Hz). 1-10

3-(1H-Indol-2-yl)-6-methyl-1H-indazole MS(M+1)=248. ¹H NMR(400 MHz,CDCl₃) δ10.34(bs, 1H), 9.73(bs, 1H), 8.36(d, 1H, J=7.9Hz), 7.71(d, 1H,J=7.8Hz), 7.61(s, 1H), 7.46(d, 1H, J=8.5Hz), 7.33(t, 1H, J=7.5Hz),7.24(d, 1H, J=8.6Hz), 7.24(t, 1H, J=7.8 Hz), 7.06(s, 1H), 2.57(s, 3H).1-11

3-(1H-Indol-2-yl)-4-chloro-1H-indazole MS(M+1)=267. ¹H NMR(400 MHz,CDCl₃) δ11.23(s, 1H), 9.06(bs, 1H), 8.11(s, 1H), 7.71 (d, 1H, J=8.0Hz),7.46(d, 1H, J=8.2Hz), 7.47-7.41(m, 3H), 7.25(t, 1H, J=8.0Hz), 7.12(s,1H). 1-12

3-(1H-Indol-2-yl)-7-chloro-1H-indazole MS(M+1)=267. ¹H NMR(400 MHz,DMSO-d₆) δ 13.88(s, 1H), 11.63(s, 1H), 8.19(d, 1H, J=9.7Hz), 7.60(d, 1H,J=9.0Hz), 7.54(d, 1H, J=8.9Hz), 7.46(d, 1H, J=9.6Hz), 7.26(t, 1H,J=9.3Hz), 7.16(s, 1H), 7.12(t, 1H, J=9.2Hz), 7.02(t, 1H, J=9.2Hz). 1-13

3-(1H-Indol-2-yl)-4-fluoro-1H-indazole MS(M+1)=251. ¹H NMR(400 MHz,DMSO-d₆) δ 13.60(s, 1H), 11.53(s, 1H), 7.59(d, 1H, J=6.6Hz),7.50-7.36(m, 3H), 7.14-6.95(m, 5H). 1-14

3-(1H-Indol-2-yl)-5-fluoro-1H-indazole MS(M+1)=251. ¹H NMR(400 MHz,DMSO-d₆) δ 13.41(s, 1H), 11.57(s, 1H), 7.97(d, 1H, J=9.1Hz), 7.64(dd,1H, J=8.6, 2.4Hz), 7.58(d, 1H, J=7.7Hz), 7.45(d, 1H, J=7.7Hz), 7.34(dt,1H, J=9.1, 1.4 Hz), 7.14(s, 1H), 7.11(t, 1H, J=7.7Hz), 7.02(t, 1H,J=7.7Hz) 1-15

3-(1H-Indol-2-yl)-5-methyl-1H-indazole MS(M+1)=248. ¹H NMR(400 MHz,DMSO-d₆) δ 13.13(s, 1H), 11.50(s, 1H), 7.94(s, 1H), 7.58(d, 1H,J=7.5Hz), 7.49 (d, 1H, J=7.8Hz), 7.44(d, 1H, J=7.8 Hz), 7.27(d, 1H,J=7.5Hz), 7.20-7.75(m, 3H), 2.52(s, 3H). 1-16

3-(1H-Indol-2-yl)-6-trifluoromethyl-1H- indazole MS(M+1)=301. ¹H NMR(400MHz, DMSO-d₆) δ 13.77(s, 1H), 11.65(s, 1H), 7.94(s, 1H), 8.85(d, 1H,J=8.5Hz), 8.00 (s, 1H), 7.63(d, 1H, J=7.7Hz), 7.53(d, 1H, J=7.7Hz),7.48(d, 1H, J=8.5Hz), 7.22(s, 1H), 7.16(t, 1H, J=7.0Hz), 7.04(t, 1H,J=7.0Hz). 1-17

3-(1H-Indol-2-yl)-5,6-dimethyl-1H- indazole MS(M+1)=261. ¹NMR(400 MHz,DMSO-d₆) δ 13.00(s, 1H), 11.45(s, 1H), 7.94(s, 1H), 7.58(d, 1H,J=7.8Hz), 7.44 (d, 1H, J=7.8Hz), 7.37(s, 1H), 7.12-7.07 (m, 2H), 7.00(t,1H, J=7.6Hz), 2.40(s, 3H), 2.38(s, 3H). 1-18

3-(1H-Indol-2-yl)-1H-indazole-6-sulfonic acid amide ¹H NMR(500 MHz,DMSO-d₆) δ 13.7(s, 1H), 11.6(s, 1H), 8.40(d, 1H, J=8.54Hz), 8.05(s, 1H),7.68(d, 1H, J=8.5Hz), 7.61 (d, 1H, J=7.8Hz), 7.48(s, 2H), 7.46(d, 1H,J=8.3Hz), 7.20(s, 1H), 7.13(t, 1H, J=7.1Hz), 7.02(t, 1H, J=7.1Hz). 1-19

3-(1H-indol-2-yl)-1H-indazole-5-sulfonamide ¹H NMR(500 MHz, DMSO-d₆) 813.7(s, 1H), 11.6(s, 1H), 8.66(s, 1H), 7.87(d, 1H, J=8.8), 7.77(d, 1H,J=8.8Hz), 7.65(d, 1H, J=7.8Hz), 7.46(d, 1H, J=8.8Hz), 7.40(s, 2H),7.14(m, 2H), 7.04(t, 1H, J=8.1Hz). 1-20

3-(1H-Indol-2-yl)-6-bromo-1H-indazole; NMR(300 MHz, CDCl₃) δ 11.20(bs,1H), 9.47(bs, 1H), 8.31(d, 1H, J=8.1Hz), 7.64 (d, 1H, J=7.8Hz),7.52-7.50(m, 2H), 7.42(dt, 1H, J=7.2, 1.5Hz), 7.32-7.26(m, 3H), 6.89(s,1H), 7.14(d, 1H, J=7.7Hz). 1-21

3-(1H-Indol-2-yl)-1H-indazole-6-carbonitrile; ¹H NMR(300 MHz, DMSO-d₆) δ13.90(s, 1H), 11.70(s, 1H), 8.42(d, 1H, J=8.1Hz), 8.25(s, 1H), 7.60(s,1H), 7.59(t, 1H, J=8.7Hz), 7.46(d, 1H, J=8.1Hz), 7.21(d, 1H, J=1.5Hz),7.14(dt, 1H, J=8.1, 1.0Hz), 7.03(dt, 1H, J=7.8, 1.0Hz).

Example 2

Step 1: 1-(Trifluoroacetyl)indoline (2-1)

To a solution of indoline (30 g, 251.74 mmol) and triethylamine (70.18mL, 503.48 mmol) in methylene chloride (500 mL) cooled to 0° C. wasadded trifluoroacetic anhydride (53.34 mL, 377.61 mmol) dropwise over 20minutes. The reaction mixture was warmed to room temperature and stirredfor 30 minutes. The solution was washed once with saturated aqueousNaHCO₃ (500 mL), dried over Na₂SO₄, then concentrated in vacuo. Theresulting solid was suspended in hexanes and collected by filtration.The solid was vacuum dried to afford 1-(trifluoroacetyl)indoline; ¹H NMR(500 MHz, CDCl₃) δ 8.22 (d, 1 H, J=8.54 Hz), 7.27 (m, 2 H), 7.16 (t, 1H, J=7.5 Hz), 4.28 (t, 2 H, J=8.3 Hz), 3.27 (t, 2 H, J=7.3 Hz).

Step 2: 1-(Trifluoroacetyl)indoline-5-sulfonyl Chloride (2-2)

A solution of the 1-(trifluoroacetyl)indoline (2-1, 21.5 g), neat inthionyl chloride (65.59 mL, 899.24 mmol), was cooled to 0° C. andtreated with chlorosulfonic acid (13.28 mL, 199.83 mmol). The solutionwas stirred for 50 minutes, then poured directly into a beaker of ice (3L). The precipitate was filtered and vacuum dried to afford1-(trifluoroacetyl)indoline-5-sulfonyl chloride (2-2) as an orangesolid; ¹H NMR (500 MHz, CDCl₃) δ 8.42 (d, 1 H, J=8.5 Hz), 8.00 (d, 1 H,J=6.7 Hz), 7.92 (s, 1 H), 4.43 (t, 2 H, J=8.2 Hz), 3.41 (t, 2 H, J=8.2Hz).

Step 3: tert-Butyl4-(2,3-dihydro-1H-indol-5-ylsulfonyl)piperazine-1-carboxylate (2-3)

A solution of 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (2-2, 5 g)in methylene chloride (50 mL) was treated with4-butoxycarbonylpiperazine (5.94 g, 31.88 mmol) and stirred for 45minutes. The brown solution was concentrated to a tan-brown solid andvacuum dried. The solid (7.4 g) was then dissolved in a mixture of1,4-Dioxane (100 mL) and Methanol (30 mL) and treated with 1N NaOH (47.9mL, 47.90 mmol). After stirring for 1 hour, the solution wasconcentrated, suspended in ethylether (130 mL) and filtered. Thefiltered solid was then partitioned between ethyl acetate (4×85 mL) andsaturated NaCl (150 mL), dried over Na₂SO₄, and concentrated to providethe tert-butyl4-(2,3-dihydro-1H-indol-5-ylsulfonyl)piperazine-1-carboxylate (2-3) asan off-white solid; ¹H NMR (300 MHz, CDCl₃) δ 7.41 (m, 2 H), 6.57 (d, 1H, J=8.9 Hz), 3.69 (t, 2 H, J=8.6 Hz), 3.50 (t, 2 H, J=4.9 Hz), 3.09 (t,2 H, J=8.6 Hz), 2.93 (t, 2 H, J=4.9 Hz), 1.42 (s, 9 H).

Step 4: tert-Butyl5-{[4(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indole-1-carboxylate(2-4)

A solution of tert-butyl4-(2,3dihydro-1H-indol-5-ylsulfonyl)piperazine-1-carboxylate (2-3, 750mg) in Methylene Chloride (50 mL) was treated with manganese dioxide(887 mg, 10.21 mmol) and stirred at reflux for 1.5 hr. An additional 5equiv (887 mg) of manganese dioxide was added and the reaction mixturewas maintained at reflux for 2 h. The mixture was cooled to roomtemperature and filtered through celite. The filter cake was washed withmethylene chloride (30 mL), ethyl acetate (30 mL), and methanol (30 mL),and the filtrate was concentrated to a tan solid. A solution of thesolid in methylene chloride (50 mL) was cooled to 0° C. and treated withdi-tert butyl dicarbonate (512 mg, 2.35 mmol) and dimethyl aminopyridine(37 mg, 0.31 mmol). The solution was mixed and slowly warmed to roomtemperature over 24 hr. The solution was partitioned between methylenechloride (2×100 mL) and water (130 mL). The combined organics were driedover Na₂SO₄, filtered and concentrated in vacuo to afford tert-butyl5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indole-1-carboxylate(2-4) as a yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 8.25 (d, 1 H, J=8.9MHz), 7.94 (s, 1 H), 7.67 (d, 1 H, J=3.7 Hz), 7.62(dd, 1 H, J=8.9Hz),6.63(d, 1 H, J=3.7 Hz), 3.44 (bt, 4 H), 2.91 (bt, 4 H), 1.62 (s, 9H), 1.32 (s, 9 H).

Step 5:1-(tert-Butoxycarbonyl)-5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indol-2-ylboronicAcid (2-5)

A solution of the tert-butyl5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indole-1-carboxylate(2-4, 1.06 g) in THF (55 mL) was stirred at −78° C. and treated witht-BuLi (1.7M, 2.68 mL, 4.55 mmol). After stirring for 45 minutes, thesolution was treated with trimethylborate (640 μL, 5.69 mmol). Thesolution was warmed to 0° C. and stirred for 10 min, then partitionedbetween ethyl acetate (2×100 mL) and saturated NH₄Cl solution (100 mL).The combined organics were dried over Na2SO4, filtered and concentratedto provide1-(tert-butoxycarbonyl)-5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indol-2-ylboronicacid (2-5) as a yellow foam. LRMS m/z: Cal'd for C₂₂H₃₂BN₃O₈S (M+H)509.39, found 510.1.

Step 6: 3-[5-(piperazin-1-ylsulfonyl)-1H-indol-2-yl]-1H-indazole (2-61

Compound 2-6 was prepared by the same chemical transformations shown inScheme 1 (1-5 to 1-7), but substituting the boronic acid 2-5, preparedas described in Step 5 for the boronic acid 1-5 in Example 1, Step 4;¹NMR (500 MHz, CD₃OD) δ 11.7 (s, 1 H), 8.18 (s, 1 H), 8.16 (d, 1 H,J=8.1 Hz), 7.67 (d, 1 H, J=8.5 Hz), 7.61 (m, 2 H, 7.47 (t, 1 H, J=6.1Hz), 7.29 (m, 2 H), 3.31 (m, 8 H).

In addition to those compounds specifically exemplified in Table 1,additional compounds in Table 2 are synthesized as shown in Scheme 1 and2. TABLE 2 # Structure Nomenclature 2-6

3-(1H-Indol-2-yl)-1H-indazol-6- ylamine 2-7

3-(1H-Indol-2-yl)-6-methoxy-1H- indazole 2-8

6-Chloro-3-(1H-indol-2-yl)-5-methyl- 1H-indazole 2-9

4-Chloro-(1H-indol-2-yl)- trifluoromethyl-1H-indazole 2-10

3-(1H-Indol-2-yl)-1H-indazole-6- carboxylic acid 2-11

3-(1H-Indol-2-yl)-1H-indazole-5- carboxylic acid 2-12

6-Chloro-3-[5-(4-methyl-piperazine- 1-sulfonyl)-1H-indol-2-yl]-1H-indazole 2-13

[2-(6-Chloro-1H-indazol-3-yl)-1H- indol-5-yl]-methanol 2-14

2-(6-Chloro-1H-indazol-3-yl)-1H- indol-5-ol 2-15

6-Chloro-3-[5-(piperazine-1- sulfonyl)-1H-indol-2-yl]-1H- indazole 2-16

6-Chloro-3-[5-(4-methyl- piperazine-1-sulfonyl)-1H-indol-2-yl]-1H-indazole 2-17

3-[5-(4-Methyl-piperazine-1- sulfonyl)-1H-indol-2-yl]-1H-indazole-6-carbonitrile

Example 3

Step 1: 6-(2-Fluoro-pyridin-4-yl)-3(1H-indol-2-yl)-1H-indazole (3-3).

A solution of the 6-bromoindazole (3-1, 97 mg, 0.235 mmol),2-fluoro-4-tributylstannanylpyridine (183 mg, 0.47 mmol),tris(dibenzylideneacetone)-dipalladium(0) (8.6 mg, 0.01 mmol),triphenylphosphine (20 mg, 0.08 mmol), and cadmium chloride (22 mg, 0.12mmol) in N-methylpyrolidinone (4 mL) was heated at 100° C. for 3 h underthe nitrogen atmosphere. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with brine,separated, dried (MgSO₄) and concentrated in vacuo. Chromatography(SiO₂, 20% ethyl acetate in hexanes) afforded the desired intermediate(3-2). The resulting N-Boc-indole (3-2) was dissolved in dichloromethane(4 mL) and treated with trifluoroacetic acid (4 mL) in the presence ofdimethylsulfide (0.05 mL) and water (0.05 ML). After 1 h stirring, thereaction mixture was concentrated in vacuo, partitioned between ethylacetate and water. The organic layer was washed with brine, separated,dried (MgSO₄) and concentrated in vacuo. Chromatography (SiO₂, 20% ethylacetate in hexanes) afforded the desired intermediate (3-3); ¹H NMR (500MHz, DMSO-d₆) δ 9.17 (bs, 1 H), 8.31 (d, 1 H, J=4.3 Hz), 8.24 (d, 1 H,J=8.5 Hz), 7.72 (d, 2 H, J=7.6 Hz), 7.54 (d, 1 H, J=8.5 Hz), 7.45 (d, 2H, 6.4 Hz), 7.22 (m, 2 H), 7.19 (t, 2 H, J=7.6 Hz).

Step 2: 4-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H-pyridin-2-one (3-4).

A solution of the fluoropyridine (3-3, 38 mg, 0.116 mmol) in 80% aceticacid in water (13 mL) was heated at 110° C. for 10 h. The reactionmixture was concentrated in vacuo, partitioned between ethyl acetate and0.5N-NaOH. The organic layer was washed with brine, separated, dried(MgSO₄) and concentrated in vacuo. Trituation of the crude solid withethyl acetate afforded the desired intermediate (3-4); ¹H NMR (500 MHz,DMSO-d₆) δ 13.5 (s, 1 H), 11.7 (bs, 1 H), 11.6 (s, 1 H), 8.28 (d, 1 H,J=8.6 Hz), 7.85 (s, 1 H), 7.60 (d, 1 H, J=7.8 Hz), 7.55 (dd, 1 H, J=8.5,1.5 Hz), 7.50 (d, 1 H, J=6.8 Hz), 7.45 (d, 1 H, J=8.1 Hz), 7.16 (d, 1 H,J=1.9Hz),7.12(dt, 1 H, J=8.1, 0.98 Hz), 7.02 (t, 1 H, J=1.9 Hz), 6.69(d, 1 H, J=1.9 Hz), 6.62 (dd, 1 H, J=6.8, 1.7 Hz).

Example 3A

A stirred solution of the pyridine (3-5) (prepared as described inExample 3, Step 1, but replacing 2-fluoro-4-tributylstannanylpyridinewith 3-tributylstannanylpyridine) in dichloromethane was treated at 0°C. with m-chlorperbenzoic acid. After 1 h stirring, the reaction mixturewas concentrated in vacuo, partitioned between ethyl acetate and water.The organic layer was washed with brine, separated, dried (MgSO₄) andconcentrated in vacuo. The crude product was treated at the ambienttemperature with 50% trifluoroacetic acid in dichloromethane in thepresence of dimethylsulfide and water. After 1 h stirring, the reactionmixture was concentrated in vacuo, partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate. The organic layer was washed withbrine, separated, dried (MgSO₄) and concentrated in vacuo.Chromatography (preparative HPLC) afforded the desired product (3-7); ¹HNMR (500 MHz, DMSO-d₆) δ 13.60 (bs, 1 H), 11.60 (s, 1 H), 8.69 (s, 1 H),8.32 (d, 1 H, J=8.5 Hz), 8.26 (d, 1 H, J=6.3 Hz), 7.46 (s, 1 H), 7.78(d, 1H, J=8.1 Hz), 7.61-7.58 (m, 2 H), 7.54 (t, 1 H, J=7.8 Hz), 7.47 (d,1 H, J=7.8 Hz), 7.18 (s, 1 H), 7.12 (t, 1 H, J=7.3 Hz), 7.03 (t, 1 H,J=7.3 Hz).

Compounds in Table 3 were synthesized as shown in Schemes 3 and 3A.TABLE 3 # Structure Nomenclature & ¹H NMR 3-8

3-(1H-Indol-2-yl)-6-(1H-pyrrol-2-yl)-1H- indazole; ¹H NMR(300 MHz,DMSO-d₆) δ 13.26(s, 1H), 11.57(s, 1H), 11.48(s, 1H), 8.13(d, 1H,J=8.7Hz), 7.76(s, 1H), 7.58(s, 1H), 7.58(t, 1H, J=8.6Hz), 7.45 (d, 1H,J=8.1Hz), 7.15-7.07(m, 2H), 7.01(t, 1H, J=7.5Hz), 6.91(m, 1H), 6.65(m,1H), 6.16(dd, 1H, J=5.1, 2.4Hz). 3-9

3-(1H-Indol-2-yl)-6-(1H-pyrrol-3-yl)-1H- indazole; ¹H NMR(300 MHz,DMSO-d₆) δ 13.10(s, 1H), 11.54(s, 1H), 11.01(s, 1H), 8.07(d, 1H,J=8.4Hz), 7.61(s, 1H), 7.59(d, 1H, J=8.7Hz), 7.49(dd, 1H, J=8.4, 1.0Hz),7.45(d, 1H, J=8.1Hz), 7.36 (m, 1H), 7.15-7.06(m, 2H), 7.01(dt, 1H,J=7.2, 1.2Hz), # 6.85(dd, 1H, J=4.5, 2.4 Hz), 6.56(dd, 1H, J=3.9,2.1Hz). 3-10

5-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H- pyridin-2-one; ¹H NMR(500 MHz,DMSO-d₆) δ 13.5(bs, 1H), 11.7(bs, 1H), 11.6(s, 1H), 8.28(d, 1H,J=8.6Hz), 7.95 (dd, 1H, J=2.7, 9.5Hz), 7.84,(d, 1H, J=2.4Hz), 7.69(s,1H), 7.59(d, 1H, J=7.5 Hz), 7.44(m, 2H), 7.12(t, 2H, J=7.3 Hz), 7.01(t,1H, J=7.3Hz), # 6.48(d, 1H, J=9.5Hz). 3-11

3-(1H-Indol-2-yl)-6-(1-oxy-pyridin-4-yl)- 1H-indazole; ¹H NMR(300 MHz,DMSO- d₆) δ 13.54(s, 1H), 11.63(s, 1H), 8.33(d, 1H, J=7.5Hz), 8.31(s,2H, J=7.8Hz), 7.95(s, 1H), 7.93(d, 1H, J=7.5Hz), 7.65(dd, 1H, J=8.4,1.5Hz), 7.61(d, 1H, J=7.8Hz), 7.46(d, 1H, J=8.1Hz), 7.18(d, 1H,J=0.9Hz), 7.13(dt, 1H, J= # 7.5 0.9Hz), 7.18(dt, 1H, J=7.5, 0.9Hz). 3-12

3-(1H-Indol-2-yl)-6-(1H-tetrazol-5-yl)-1H- indazole; ¹H NMR(300 MHz,DMSO-d₆) δ 13.72(s, 1H), 11.67(s, 1H), 8.45(d, 1H, J=8.7Hz), 8.30(s,1H), 7.93(dd, 1H, J=8.7, 1.2Hz), 1.62(d, 1H, J=7.5Hz), 7.47(d, 1H,J=8.4Hz), 7.22(s, 1H), # 7.14(dt, 1H, J=8.4, 1.2Hz), 7.03(dt, 1H, J=7.4,1.2Hz).

In addition to compounds in Table 3, additional compounds in Table 3Aare synthesized as shown in Schemes 3 and 3A. TABLE 3A # StructureNomenclature 3-13

3-(1H-Indol-2-yl)-6-pyridin-3-yl-1H- indazole 3-14

3-(1H-Indol-2-yl)-6-pyridin-4-yl-1H- indazole 3-15

3-(1H-Indol-2-yl)-6-(3-methoxy- phenyl)-1H-indazole 3-16

3-(1H-Indol-2-yl)-6-(2-methoxy-pyridin- 4-yl)-1H-indazole 3-17

6-(1H-Imidazol-4-yl)-3-(1H-indol-2-yl)- 1H-indazole 3-18

6-(1H-Imidazol-2-yl)-3-(1H-indol-2-yl)- 1H-indazole

Example4

Step 1:2-(6-Chloro-1H-indazol-3-yl)-5-(isopropyl-dimethyl-silanyloxymethyl)-indole-1-carboxylicAcid tert-butyl Ester (4-3).

A biphasic reaction mixture of the iodide (1-4b, 1 g, 3.59 mmol), theboronic acid (4-1, 2.47 g, 6.10 mmol),tetrakis(triphenylphosphine)palladium(0) (208 mg, 0.18 mmol), lithiumchloride (457 mg, 10.8 mmol), and Na₂CO₃ (2M, 9 mL) in dioxane (27 mL)was heated at 80° C. for 2 h under the nitrogen atmosphere. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, separated, dried (MgSO₄) and concentratedin vacuo. Chromatography (SiO₂, 33% ethyl acetate in hexanes) followedby concentration afforded 4-2 as a pale brown solid. The intermediate,4-2, was dissolved in dichloromethane (6 mL) and treated at the ambienttemperature with triethylammonium fluoride (1.74 g, 10.77 mmol). After 3h stirring, the reaction mixture was concentrated in vacuo andpartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution. The organic layer was separated, dried (MgSO₄),and concentrated in vacuo. Chromatography (SiO₂, 33% ethyl acetate inhexanes) followed by concentration afforded 4-3 as a pale brown solid.;MS (M+1)=398.

Step 2: 2-(6-Chloro-1H-indazol-3-yl)-indole-1,5-dicarboxylic Acid1-tert-butyl ester (4-5)

A solution of the alcohol 4-3 (210 mg, 0.528 mmol) in dichloromethanewas treated with manganese dioxide (229 mg, 2.64 mmol) and heated toreflux where it remained for 1 h. Five additional equivalents ofmanganese dioxide were added and the reaction was maintained at refluxfor 1 h. The excess manganese dioxide was filtered through Celite andthe filter cake was washed with ethyl acetate (40 ml) and methanol (40ml). The filtrate was concentrated in vacuo to a brown oil (4-4). Asolution of the tert-butyl5-formyl-2-(1H-indazol-3-yl)-1H-indole-1-carboxylate (4-4,1.2 g, 3.3mmol), 2-methyl-2-butene (19.9 ml, 188.2 mmol), a 1.9M solution ofsodium phosphate monobasic (1.73 ml, 6.6 mmol), and sodium chlorite(597.3 mg, 6.60 mmol) were stirred in t-Butanol for 1 h. 3 additionalequivalents of both solid sodium phosphate monobasic and sodium chloritewere added to the reaction over a 3 h period, and the reaction was mixedfor 24 h. The t-Butanol was removed in vacuo and the residual yellowsolid was dissolved in ethyl acetate (150 ml) and washed twice with a98:2 mixture of 10% sodium bisulfite:10% potassium bisulfate (2×75 ml).The combined organics were dried over Na₂SO₄, filtered and concentratedin vacuo to afford1-(tert-butoxycarbonyl)-2-(1H-indazol-3-yl)-1H-indole-5-carboxylic acid(4-5); ¹H NMR(500 MHz, CDCl₃) δ 8.47 (s, 1 H), 8.40 (d, 1 H, J=8.8 Hz),8.17 (d, 1 H, J=8.8 Hz), 7.68 (d, 1 H, J=8.1 Hz), 7.56 (d, 1 H, J=8.3Hz), 7.46 (t, 1 H, J=8.3 Hz), 7.23 (t, 1 H, J=7.8 Hz), 6.99 (s, 1 H),1.14 (s, 3H).

Step 3:3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}-1H-indazole(3-6a).

A solution of1-(tert-butoxycarbonyl)-2-(1H-indazol-3-yl)-1H-indole-5-carboxylic acid(4-5, 100 mg, 0.265 mmol), N-methyl piperazine (40 μL, 0.32 mmol), EDC(61 mg, 0.32 mmol), and HOAt (43.3 mg, 0.32 mmol)in 5 ml of DMF wastreated with triethylamine (90 μL, 0.66 mmol) and mixed for 24 h. Thesolution was partitioned between ethyl acetate (3×50 mL) and water (75mL). The combined organics were dried over Na₂SO₄, filtered andconcentrated. The residual oil was dissolved in a 1:1 mixture ofdichloromethane/trifluoroacetic acid and mixed for 45 min. The solventwas removed in vacuo and the residue was purified by reverse phaseliquid chromatography (H₂O/CH₃CN gradient with 0.1% 1TA present) toprovide3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}-1H-indazole(4-6); ¹H NMR (500 MHz, CD₃OD) δ 11.36 (s, 1 H), 8.14 (d, 1 H, J=8.3Hz), 7.83 (s, 1 H), 7.58 (dd, 2 H, J=8.5 Hz), 7.45 (t, 1 H, J=8.3 Hz),7.30 (dd, 2 H, J=8.06 Hz), 7.17 (s, 1H), 4.55 (bs, 2 H), 3.45 (bs, 2 H),3.25 (bs, 2 H), 2.98 (s, 3 H).

Compounds in Table 5 were synthesized as shown in Scheme 4. TABLE 5 #Structure Nomenclature & ¹H NMR 4-7

1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]-1-(4-methyl-piperazin-1-yl)-methanone; ¹H NMR(500 MHz, CD₃OD) δ 11.36(s, 1H), 8.14(d, 1H, J=8.3Hz), 7.83 (s, 1H), 7.59(d, 1H, J=8.6Hz), 7.56(d, 1H, J=8.6Hz), 7.46(t, 1H, J=8.3Hz), 7.31-7.27(m, 2H), 7.17(s, 1H),4.55(bs, 2H), 3.43(bs, 4H), 3.22 # (bs, 2H), 2.98(s, 3H). 4-8

1-[2-(6-Chloro-1H-indazol-3-yl)-1H- indol-5-yl]-1-piperazin-1-yl-methanone; ¹H NMR(500 MHz, CD₃OD) δ 11.41(s, 1H), 8.12(d, 1H, J=8.5Hz),7.83(d, 1H, J=0.74Hz), 7.61(d, 1H, J=1.2Hz), 7.56(d, 1H, J=8.3Hz),7.30(dd, 1H, J=8.3, 1.5 Hz), 7.26(dd, 1H, J=8.5, 1.7Hz), 7.17(s, 1H),3.93(m, 4H), 3.31(m, 4H). 4-9

1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]- 1-piperazin-1-yl-methanone; ¹HNMR (500 MHz, CD₃OD) δ 11.34(s, 1H), 8.14(d, 1H, J=8.3Hz), 7.83(d, 1H,J=0.7Hz), 7.58(d, 1H, J=8.3Hz), 7.56(d, 1H, J=8.3Hz), 7.45(dt, 1H,J=7.7, 1.1Hz), 7.31-7.26(m, 2H), 7.17(s, 1H), 3.94(m, 4 H), 3.32(m, 4H).

In addition to compounds in Table 5, additional compounds in Table 6 aresynthesized as shown in Scheme 4. TABLE 6 # Structure Nomenclature 4-10

1-[2-(6-Chloro-1H-indazol-3-yl)- 1H-indol-6-yl]-1-(4-methyl-piperazin-1-yl)-methanone 4-11

1-[2-(6-Chloro-1H-indazol-3-yl)- 1H-indol-4-yl]-1-(4-methyl- piperazin-1-yl)-methanone 4-12

1-(3-Amino-pyrrolidin-1-yl)-1-[2- (6-chloro-1H-indazol-3-yl)-1H-indol-5-yl]-methanone 4-13

2-(6-Chloro-1H-indazol-3-yl)-1H- indole-5-carboxylic acid methylamide

Example 5

Step 1: 6-Chloro-3-ethynyl-1H-indazole (5-2)

A 12-inch pressure tube was charged with 6-Chloro-3-ethynyl-1H-indazole(1-4b, 4.0 g, 14.4 mmol), tetrakis(triphenylphosphine)palladium(0) (500mg, 0.43 mmol), and cuprous iodide (82 mg, 0.43 mmol). The solids weredissolved/suspended in acetonitrile (10 mL) and triethylamine (10 mL,71.8 mmol) followed by bubbling with nitrogen to degas the mixture. Thetrimethylsilyl acetylene (2.44 mL, 17.2 mmol) was added via pipette andthe vessel was sealed before heated in an oil bath to 80° C. Thereaction tube was cooled to ambient temperature after 2 h andpartitioned between ethyl acetate and water. The layers were separatedand the aqueous was extracted twice with ethyl acetate. The organicswere combined, washed with brine, dried over magnesium sulfate, vacuumfiltered, and concentrated in vacuo to afford the crude product as ablack oil. The oil was dissolved in ethanol (50 mL) and 2M-KOH solution(30 mL). The deprotection was completion after 4 h at ambienttemperature. The reaction mixture was concentrated in vacuo andpartitioned between ethyl acetate and water. The layers were separatedand the aqueous was extracted several times with ethyl acetate. Theorganics were combined, washed with brine, dried over sodium sulfate,vacuum filtered, and concentrated in vacuo to afford the crude productas a brown oil. This residue was purified by flash chromatography inhexanes/ethyl acetate gradients to give 5-2 as a yellow-orange powder.;¹H NMR (300 MHz, DMSO-d₆) δ 13.57 (bs, 1 H), 7.74 (d, 1 H, J=8.4 Hz),7.70 (d, 1 H, J=1.8 Hz), 7.24 (dd, 1 H, J=8.7, 1.5 Hz), 4.57 (s, 1 H).

Step 2: 4-Amino-3-(6-chloro-1H-indazol-3-ylethynyl)-benzenesulfonamide(5-4).

A mixture of the alkyne (5-2, 300 mg, 1.01 mmol), the iodide (5-3, 300mg, 1.01 mmol), tetrakis(triphenylphosphine)palladiun(0) (35 mg, 0.03mmol), cuprous iodide (6 mg, 0.03 mmol) in acetonitrile (1.4 mL) andtriethylamine (0.7 mL) in a thick-walled tube was heated at 80° C. for 5h. The reaction mixture was cooled to the ambient temperature and theresulting precipitates (5-4) were collected by filtration as a light tansolid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.64 (s, 1 H), 7.94 (d, 1 H, J=8.4Hz), 7.76 (d, 1 H, J=2.1 Hz), 7.71 (d, 1 H, J=1.5 Hz), 7.53 (dd, 1 H,J=8.7, 2.1 Hz), 7.26 (dd, 1 H, J=8.4, 1.5 Hz), 7.08 (bs, 2 H), 6.84 (d,1 H, J=8.4 Hz), 6.27 (bs, 2 H).

Step 3: 2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic Acid Amide(5-5).

The alkyne (5-4, 56 mg, 0.161 mmol) was dissolved in acetic acid (8 mL)and treated with mercuric acetate (77 mg, 0.24 mmol). After 2 hstirring, the reaction mixture was concentrated in vacuo, suspended insaturated aqueous sodium bicarbonate and treated with sodiumborohydride. After 10 min stirring, the mixture was extracted with ethylacetate. The organic layer was washed with brine, separated, dried(MgSO₄) and concentrated in vacuo. Chromatography (SiO₂, 50% ethylacetate in hexanes) afforded the desired product (5-5); ¹H NMR (300 MHz,DMSO-d₆) δ 13.58 (s, 1 H), 12.09 (s, 1 H), 8.26 (d, 1 H, J=8.7 Hz), 8.11(s, 1 H), 7.72 (d, 1 H, J=1.5 Hz), 7.61 (dd, 1 H, J=8.7, 1.8 Hz), 7.55(d, 1 H, J=8.4 Hz), 7.36 (d, 1 H, J=1.5 Hz), 7.30 (dd, 1 H, J=8.7, 1.8Hz), 7.16 (s, 2 H).

Compounds in Table 7 were synthesized as shown in Scheme 5. TABLE 7 #Structure Nomenclature 5-6

Methyl [2-(6-chloro-1H-indazol-3-yl)- 1H-indole-5-yl]sulfone; ¹H NMR(300MHz, DMSO-d₆) δ 13.63(s, 1H), 12.24(s, 1H), 8.25(d, 1H, J=8.7 Hz),7.19(s, 1H), 7.73(d, 1H, J=1.5 Hz), 7.68-7.62(m, 2H), 7.40(d, 1H,J=1.8Hz), 7.32(dd, 1H, J=8.4, 1.8 Hz), 3.19(s, 3H) 5-7

2-(6-Chloro-1H-indazol-3-yl)-7-fluoro- 1H-indole-5-sulfonic acid amide;¹H NMR(300 MHz, DMSO-d₆) δ 13.66 (s, 1H), 12.61(d, 1H, J=1.2Hz), 8.23(d,1H, J=8.7Hz), 7.96(d, 1H, J=1.2Hz), 7.73(d, 1H,J=1.2Hz), 7.44(dd, 1H,J=3.0, 2.1Hz), 7.39(dd, # 1H, J=10.8, 1.2Hz), 7.31(dd, 1H, J=9.0,1.8Hz), 7.30(s, 2H). 5-8

2-(6-Chloro-1H-indazol-3-yl)-6-fluoro- 1H-indole-5-sulfonic acid amide;¹H NMR(300 MHz, DMSO-d₆) δ 13.59 (s, 1H), 12.14(s, 1H), 8.23(d, 1H,J=9.0Hz), 8.05(d, 1H, J=7.5Hz), 7.72(d, 1H, J=1.2Hz), 7.44(s, 2H),7.37(d, 1H, J=1.2Hz), 7.32(m, 1H), 7.29(s, 1H). 5-9

2-(6-Chloro-1H-indazol-3-yl)-4- fluoro-1H-indole-5-sulfonic acid amide;¹H NMR(300 MHZ, DMSO- d₆) δ 13.65(s, 1H), 12.35(s, 1H), 8.34(d, 1H,J=9.0Hz), 7.73(d, 1H, J=1.5Hz), 7.52(dd, 1H, J=8.4, 6.9 Hz), 7.46(s,2H), 7.37(d, 1H, J=1.2 Hz), 7.29(dd, 1H, J=9.0, 1.8Hz). 5-10

7-Chloro-2-(6-chloro-1H-indazol-3- yl)-1H-indole-5-sulfonic acid amide;¹H NMR(300 MHz, DMSO-d₆) δ13.67(s, 1H), 12.32(s, 1H), 8.19(d, 1H,J=8.4Hz), 8.08(d, 1H, J=1.2 Hz), 7.74(d, 1H, J=1.5Hz), 7.65(d, 1H,J=1.5Hz), 7.44(d, 1H, J=1.8 Hz), 7.33-7.30(m, 3H). 5-11

2-(6-Chloro-5-fluoro-1H-indazol-3- yl)-1H-indole-5-sulfonic acid amide;¹H NMR(500 MHz, DMSO-d₆) δ13.70(s, 1H), 12.1(s, 1H), 8.29(d, 1H,J=9.5Hz), 8.09(d, 1H, J=1.5 Hz), 7.90(d, 1H, J=6.1Hz), 7.61 (dd, 1H,J=1.7, 8.5Hz), 7.55(d, 1H, J=8.5Hz), 7.41(d, 1H, J=1.5 Hz), 7.16(s, 2H).5-12

2-(6-Chloro-1H-indazol-3-yl)-1H- indole-5-carboxylic acid methyl ester;¹H NMR(300 MHz, DMSO-d₆) δ 13.55 (s, 1H), 12.45(s, 1H), 8.28(s, 1H),8.25(d, 1H, J=8.4Hz), 7.86(d, 1H, J=8.7Hz), 7.72(d, 1H, J=1.8Hz), 7.49(d, 1H, J=8.4Hz), 7.3-7.25(m, 2H), 3.75(s, 3H). 5-13

2-(6-chloro-1H-indazol-3-yl)-1H-indole- 5-carboxylic acid; ¹H NMR(300MHz, DMSO-d₆) δ 13.55(s, 1H), 12.45(s, 1H), 12.02(s, 1H), 8.28(s, 1H),8.25(d, 1H, J=8.4Hz), 7.75(dd, 1H, J=8.7, 1.5Hz), 7.72(d, 1H, J=1.8Hz),7.49 (d, 1H, J=8.4Hz), 7.31(d, 1H, J=2.1 Hz), 7.29(dd, 1H, J=9.0,1.8Hz). 5-14

6-Chloro-3-(5-fluoro-1H-indol-2-yl)-1H- indazole; ¹H NMR(400 MHz, DMSO-d₆) δ 13.48 (s, 1H), 11.72(s, 1H), 8.20 (d, 1H, J=8.3Hz), 7.50(s, 1H),7.42 (dd, 1H, J=8.6, 4.3Hz), 7.33(dd, 1H, J=9.7, 2.5Hz), 7.29(d, 1H,J=8.0 Hz), 7.14(s, 1H), 6.97(dt, 1H, J=9.0, 2.5Hz). 5-15

6-Chloro-3-(5-methyl-1H-indol-2-yl)- 1H-indazole; ¹H NMR(400 MHz,DMSO-d₆) δ 13.40(s, 1H), 11.43(s, 1H), 8.20(d, 1H, J=8.9Hz), 7.68(s,1H), 7.37(s, 1H), 7.34(d, 1H, J=8.3Hz), 7.25(d, 1H, J=8.6Hz), 7.04(s,1H), 6.95(d, 1H, J=8.3Hz), 2.39(s, 3H).

In addition to compounds in Table 7, additional compounds in Table 8 aresynthesized as shown in Scheme 5. TABLE 8 # Structure Nomenclature 5-16

2-(6-Chloro-1H-indazol-3-yl)-1H- indole-6-sulfonic acid amide 5-17

2-(6-Chloro-1H-indazol-3-yl)-1H- indole-4-sulfonic acid amide 5-18

2-(6-Chloro-1H-indazol-3-yl)-5- fluoro-1H-indole-4-sulfonic acid amide5-19

1-[2-(6-Chloro-1H-indazol-3-yl)- 1H-indol-5-yl]-2-hyroxy- ethanone

Example 6

Step 1: [2-(1H-Indazol-3-yl)-1H-indol-5-yl]-methanol (6-2).

To a stirred solution of the methyl ester (6-1, 90 mg, 0.309 mmol) intetrahydrofuran (3 mL) was added at −78° C. a solution of lithiumaluminium hydride in toluene (1M, 0.62 mL, 0.62 mmol). The reactionmixture was stirred at the ambient temperature for 3 h, partitionedbetween ethyl acetate and 0.2N-hydrochloric acid. The organic layer waswashed with brine, separated, dried (MgSO₄) and concentrated in vacuo.Chromatography (SiO₂, 60% ethyl acetate in hexanes) afforded the desiredproduct (6-2) as a light tan solid; ¹H NMR (400 MHz, DMSO-d₆) δ 13.28(s, 1 H), 11.49 (s, 1 H), 8.19 (d, 1 H, J=8.4 Hz), 7.60 (d, 1 H, J=8.4Hz), 7.53 (s, 1 H), 7.44 (dt, 1 H, J=7.6, 1.2 Hz), 7.39 (d, 1 H, J=8.4Hz), 7.25 (dt, 1 H, J=8.0, 0.8 Hz), 7.10-7.08(m, 2H),5.0 (t, 1 H,J=5.6Hz), 4.56 (d, 2H, J=5.6 Hz).

Step 2: 2-(1H-Indazol-3-yl)-1H-indole-5-carbaldehyde (6-3).

To a stirred solution of the alcohol (6-2,29 mg, 0.11 mmol) intetrahydrofuran (2 mL) was added at the ambient temperature2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75 mg, 0.33 mmol). After 5 hstirring, the reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with brine, separated, dried (MgSO₄)and concentrated in vacuo. Chromatography (SiO₂, 50% ethyl acetate inhexanes) afforded the desired product (6-3) as a light tan solid; ¹H NMR(400 MHz, DMSO-d₆) δ 13.42 (s, 1 H), 11.14 (s, 1 H), 9.98 (s, 1 H), 8.22(d, 1 H, J=8.4 Hz), 8.20 (s, 1 H), 7.70-7.56 (m, 3 H), 7.46 (t, 1 H,J=7.8 Hz), 7.36 (s, 1 H),7.28 (t, 1 H, J=7.8 Hz).

Step 3: 3-[5-(4-Methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole(6-4)

A mixture of the aldehyde (6-3, 50 mg, 0.19 mmol), N-methylpiperazine(191 mg, 1.91 mmol), acetic acid (0.06 mL) and sodiumtriacetoxyborohydride (406 mg, 1.91 mmol) in N,N-dimethyl formamide (3mL) was stirred at the ambient temperature for 11 h. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, separated, dried (MgSO₄) and concentratedin vacuo. Chromatography (SiO₂, 30% methanol in ethyl acetate) affordedthe desired product (6-4) as a light tan solid; ¹H NMR (400 MHz,DMSO-d₆) δ 13.34 (s, 1 H), 11.56 (s, 1 H), 8.23 (d, 1 H, J=8.0 Hz), 7.66(d, 1 H, J=8.4 Hz), 7.53 (s, 1 H), 7.49 (t, 1 H, J=7.6 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.31 (t, 1 H, J=7.6 Hz), 7.12-7.11 (m, 2 H), 3.57 (s, 2H), 2.52-2.26 (m, 8 H), 2.21 (s, 3H).

Compounds in Table 9 were synthesized as shown in Scheme 6. TABLE 9 #Structure Nomenclature & ¹H-NMR 6-5

3-[5-(4-Methanesulfonyl-piperazin-1- ylmethyl)-1H-indol-2-yl]-1H-indazole; ¹H NMR(300 MHz, DMSO-d₆) δ 13.31(s, 1H), 11.56(s, 1H), 8.18(d,1H, J=8.1Hz), 7.61 (d, 1H, J=8.1Hz), 7.50(s, 1H), 7.45(d, 1H, J=6.9Hz),7.40(d, 1H, 9.0Hz), 7.26(t, 1H, 7.5 Hz), 7.09(s, 1H), 7.08(m, 1H), 3.58# (s, 2H), 3.11(bs, 4H), 2.87(s, 3H), 2.50(m, 4H). 6-6

6-Chloro-3-[5-(4-methanesulfonyl- piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole; ¹H NMR(300 MHz, DMSO-d₆) δ 13.45(s, 1H), 11.61(s, 1H),8.21(d, 1H, J=8.7Hz), 7.69 (d, 1H, J=1.5Hz), 7.49(s, 1H), 7.40(d, 1H,J=8.7Hz), 7.27(dd, 1H, J=8.4, 1.8Hz), 7.11(s, 1H), 7.09 (dd, 1H, J=8.4,1.2Hz), 3.58(s, # 2H), 3.11(bs, 4H), 2.87(s, 3 H), 2.50 (m, 4H). 6-7

6-Chloro-3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole; ¹H NMR(300 MHz, DMSO-d₆) δ 13.45(s, 1H), 11.60(s, 1H), 8.21(d, 1H, J=8.7Hz), 7.69(d, 1H,J=1.2Hz), 7.49(s, 1H), 7.40(d, 1H, J=8.1Hz), 7.26 (dd, 1H, J=8.4, 1.5Hz), 7.11(s, 1H),7.09(m, 1H), 3.55(s, 2H), 3.42(m, 4H), # 2.38(t, 2H, J=4.8Hz), 3.32(t,2H, J=4.8Hz), 1.97(s, 3H). 6-8

1-[2-(6-Chloro-1H-indazol-3-yl)-1H- indol-5-ylmethyl]-4-methyl-[1,4]diazepan-5-one; ¹H NMR(300 MHz, DMSO-d₆) δ 13.45(s, 1H), 11.60 (s,1H), 8.21(d, 1H, J=8.7Hz), 7.69 (d, 1H, J=1.2Hz), 7.48(s, 1H), 7.40 (d,1H, J=8.1Hz), 7.26(dd, 1H, J=8.4, 1.5Hz), 7.10(s, 1H), 7.06(m, 1H), #3.62(s, 2 H), 3.43(m, 2 H), 2.83(s, 3H), 2.60-2.44(m, 6H). 6-9

1-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-pipetazin-1-yl}-2- hydroxy-ethanone; ¹H NMR(300 MHz,DMSO-d₆) δ 13.47(s, 1H), 11.60(s, 1H), 8.21(d, 1H, J=8.7Hz), 7.69(d, 1H,J=1.5Hz), 7.49(s, 1H), 7.39(d, 1H, J=8.1Hz), 7.26(dd, 1H, J=8.7, 1.8Hz),7.11(s, 1H), 7.09(m, 1H), # 4.53(t, 1H, J=5.7Hz), 4.06(d, 2H, J=5.7Hz),3.56(s, 2H), 3.47(bs, 2H), 3.33(bs, 2H), 2.37(bs, 4H). 6-10

3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}- butyric acid; ¹H NMR(300 MHz,DMSO-d₆) δ 13.51(s, 1H), 11.69(br s, 1H), 8.22(d, 1H, J=9.0Hz), 7.70(d,1H, J=1.8Hz), 7.58(brs, 1H), 7.43 (d, 1H, J=8.1Hz), 7.27(dd, 1H, J= #8.7, 1.8Hz), 7.15(br s, 2H), 3.33(br s, 6H), 3.12(m, 1H), 2.67(brs, 4H),2.47(m, 1H) 2.18(dd, 1H, J=15.6, 6.9Hz), 1.01(d, 3H, J=6.9Hz). 6-11

6-Chloro-3-[4-(4-methanesulfonyl- piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole; ¹H NMR(300 MHz, DMSO-d₆) δ 13.45(s, 1H), 11.64(s, 1H),8.26(d, 1H, J=8.7Hz), 7.69(d, 1H, J=1.2Hz), 7.36(d, 1H, J=8.1 Hz),7.29(dd, 1H, J=8.7, 1.5Hz), 7.27(s, 1H), 7.09(t, 1H, J=7.2Hz), # 6.98(d,1H, J=6.9Hz), 3.86(s, 2H), 3.13(m, 4H) 2.86(s, 3H), 2.58(m, 4H). 6-12

3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-4-ylmethyl]-piperazin-1-yl}- butyric acid; ¹H NMR(300 MHz,DMSO-d d₆) δ 13.45(s, 1H), 11.64(s, 1H), 8.26(d, 1H, J=8.7) δ 13.56(s,1H), 11.87(brs, 1H), 8.35(d, 1H, J=8.4Hz), 7.71(d, 1H, J=1.2Hz), 7.50(br s, 2H), 7.31(dd, 1H, J=8.4, 1.2 #Hz), 7.19(br s, 2H), 4.61(br s,2H), 3.09(br s, 4H) 2.92(br s, 4H), 2.73-2.44(m, 2H), 2.21(m, 1H),1.02(br s, 3H).

In addition to compounds in Table 9, additional compounds in Table 10are synthesized as shown in Scheme 6. TABLE 10 # Structure Nomenclature6-10

4-[2-(6-Chloro-1H-indazol-3- yl)-1H-indol-5-ylmethyl]-piperazine-1-carboxylic acid methylamide 6-11

6-Chloro-3-[6-(4- methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H- indazole 6-12

3-[5-(4-Methanesulfonyl- piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole-6- carbonitrile 6-15

3-{4-[2-(6-Cyano-1H-indazol- 3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-butyric acid

1. A compound of Formula I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

W is N or C; X═Y is C═N, N═C, or C═C; a is 0 or 1; b is 0 or 1; m is 0,1, or 2; t is 1,2, or 3; R¹, R² and R⁵ are independently selectedfrom: 1) H, 2) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 3) (C═O)_(a)O_(b)aryl, 4)(C═O)_(a)O_(b)C₂-C₁₀ alkenyl, 5) (C═O)_(a)O_(b)C₂-C₁₀ alkynyl, 6) CO₂H,7) halo, 8) OH, 9) O_(b)C₁-C₆ perfluoroalkyl, 10) (C═O)_(a)NR⁷R⁸, 11)CN, 12) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, 13) (C═O)_(a)O_(b)heterocyclyl,14) SO₂NR⁷R⁸, and 15) SO₂C₁-C₁₀ alkyl, said alkyl, aryl, alkenyl,alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with oneor more substituents selected from R⁶; R³ is selected from: 1) H, 2)(C═O)O_(a)C₁-C₆ alkyl, 3) (C═O)O_(a)aryl, 4) C₁-C₆ alkyl, 5) SO₂R^(a),and 6) aryl; R⁴ is selected from: 1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2)(C═O)_(a)O_(b)aryl, 3) (C═O)_(a)O_(b)C₂-C₁₀ alkenyl, 4)(C═O)_(a)O_(b)C₂-C₁₀ alkynyl, 5) CO₂H, 6) halo, 7) OH, 8) O_(b)C₁-C₆perfluoroalkyl, 9) (C═O)_(a)NR⁷R⁸, 10) CN, 11) (C═O)_(a)O_(b)C₃-C₈cycloalkyl, 12) (C═O)_(a)O_(b)heterocyclyl, 13) SO₂NR⁷R⁸, and 14)SO₂C₁-C₁₀ alkyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, andheterocyclyl is optionally substituted with one or more substituentsselected from R⁶; R⁶ is: 1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2)(C═O)_(a)O_(b)aryl, 3) C₂-C₁₀ alkenyl, 4) C₂-C₁₀ alkynyl, 5)(C═O)_(a)O_(b)heterocyclyl, 6) CO₂H, 7) halo, 8) CN, 9) OH, 10)O_(b)C₁-C₆ perfluoroalkyl, 11) O_(a)(C=O)_(b)NR⁷R⁸, 12) oxo, 13) CHO,14) (N═O)R⁷R⁸, or 15) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one or more substituents selected from R^(6a); R^(6a) is selectedfrom: 1) (C═O)_(r)O_(s)(C₁-C₁₀ )alkyl, wherein r and s are independently0 or 1, 2) O_(r)(C₁-C₃)perfluoroalkyl, wherein r is 0 or 1, 3)(C₀-C₆)alkylene-S(O)_(m)R^(a), wherein m is 0, 1, or 2, 4) oxo, 5) OH,6) halo, 7) CN, 8) (C₂-C₁₀)alkenyl, 9) (C₂-C₁₀)alkynyl, 10)(C₃-C₆)cycloalkyl, 11) (C₀-C₆)alkylene-aryl, 12)(C₀-C₆)alkylene-heterocyclyl, 13) (C₀-C₆)alkylene-N(R^(b))₂, 14)C(O)R^(a), 15) (C₀-C₆)alkylene-CO₂R^(a), 16) C(O)H, 17)(C₀-C₆)alkylene-CO₂H, and 18) C(O)N(R^(b))₂, said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substitutedwith up to three substituents selected from R^(b), OH, (C₁-C₆)alkoxy,halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂; R⁷ and R⁸ areindependently selected from: 1) H, 2) (C=O)O_(b)C₁-C₁₀ alkyl, 3)(C=O)O_(b)C₃-C₈ cycloalkyl, 4) (C=O)O_(b)aryl, 5)(C=O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8) C₂-C₁₀ alkenyl, 9)C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈ cycloalkyl, 12) SO₂R^(a),and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl, aryl, heterocylyl,alkenyl, and alkynyl is optionally substituted with one or moresubstituents selected from R^(6a), or R⁷ and R⁸ can be taken togetherwith the nitrogen to which they are attached to form a monocyclic orbicyclic heterocycle with 5-7 members in each ring and optionallycontaining, in addition to the nitrogen, one or two additionalheteroatoms selected from N, O and S, said monocylcic or bicyclicheterocycle optionally substituted with one or more substituentsselected from R^(6a); R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, orheterocyclyl; and R^(b) is H, (C₁-C₆)alkyl, aryl, heterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a). 2.The compound of claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein


3. A compound of Formula I

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

a is 0 or 1; b is 0 or 1; and t is 1 or 2; R¹, R² and R⁵ areindependently selected from: 1) H, 2) (C═O)_(a)O_(b)C₁-C₆ alkyl, 3)(C═O)_(a)O_(b)aryl, 4) (C═O)_(a)O_(b)C₂-C₆ alkenyl, 5)(C═O)_(a)O_(b)C₂-C₆ alkynyl, 6) CO₂H, 7) halo, 8) OH, 9) O_(b)C₁-C₃perfluoroalkyl, 10) (C═O)_(a)NR⁷R⁸, 11)CN, 12) (C═O)_(a)O_(b)C₃-C₆cycloalkyl, 13) (C═O)_(a)O_(b)heterocyclyl, 14) SO₂NR⁷R⁸, and 15)SO₂C₁-C₆ alkyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, andheterocyclyl is optionally substituted with one or more substituentsselected from R⁶; R⁴ is selected from: 1) (C═O)_(a)O_(b)C₁-C₆ alkyl, 2)(C═O)_(a)O_(b)aryl, 3) (C═O)_(a)O_(b)C₂-C₆ alkenyl, 4)(C═O)_(a)O_(b)C₂-C₆ alkynyl, 5) CO₂H, 6) halo, 7) OH, 8) O_(b)C₁-C₃perfluoroalkyl, 9) (C═O)_(a)NR⁷R⁸, 10) CN, 11) (C═O)_(a)O_(b)C₃-C₆cycloalkyl, 12) (C═O)_(a)O_(b)heterocyclyl, 13) SO₂NR⁷R⁸, and 14)SO₂C₁-C₆ alkyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, andheterocyclyl is optionally substituted with one or more substituentsselected from R⁶; R⁶ is: 1) (C═O)_(a)O_(b)C₁-C₆ alkyl, 2)(C═O)_(a)O_(b)aryl, 3) C₂-C₆ alkenyl, 4) C₂-C₆ alkynyl, 5)(C═O)_(a)O_(b)heterocyclyl, 6) CO₂H, 7) halo, 8) CN, 9) OH, 10)O_(b)C₁-C₃ perfluoroalkyl, 11) O_(a)(C═O)_(b)NR⁷R⁸, 12) oxo, 13) CHO,14) (N═O)R⁷R⁸, or 15) (C═O)_(a)O_(b)C₃-C₆ cycloalkyl, said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl is optionally substitutedwith one or more substituents selcted from R^(6a); R^(6a) is selectedfrom: 1) (C═O)_(r)O_(s)(C₁-C₆)alkyl, wherein r and s are independently 0or 1, 2) O_(r)(C₁-C₃)perfluoroalkyl, wherein r is 0 or 1, 3)(C₀-C₆)alkylene-S(O)_(m)R^(a), wherein m is 0, 1, or 2, 4) oxo, 5) OH,6) halo, 7) CN, 8) (C₂-C₆)alkenyl, 9) (C₂-C₆)alkynyl, 10)(C₃-C₆)cycloalkyl, 11) (C₀-C₆)alkylene-aryl; 12)(C₀-C₆)alkylene-heterocyclyl, 13) (C₀-C₆)alkylene-N(R^(b))₂, 14)C(O)R^(a), 15) (C₀-C₆)alkylene-CO₂R^(a), 16) C(O)H, and 17)(C₀-C₆)alkylene-CO₂H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,and heterocyclyl is optionally substituted with up to three substituentsselected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆alkyl, oxo, and N(R^(b))₂; and R⁷ and R⁸ are independently selectedfrom: 1) H, 2) (C═O)O_(b)C₁-C₆ alkyl, 3) (C═O)O_(b)C₃-C₆ cycloalkyl, 4)(C═O)O_(b)aryl, 5) (C═O)O_(b)heterocyclyl, 6) C₁-C₆ alkyl, 7) aryl, 8)C₂-C₆ alkenyl, 9) C₂-C₆ alkynyl, 10) heterocyclyl, 11) C₃-C₆ cycloalkyl,12) SO₂R^(a), and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl, aryl,heterocylyl, alkenyl, and alkynyl is optionally substituted with one ormore substituents selected from R6^(a), or R⁷ and R⁸ can be takentogether with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocylcic orbicyclic heterocycle optionally substituted with one or moresubstituents selected from R^(6a); R^(a) is (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, aryl, or heterocyclyl; and R^(b) is H, (C₁-C₆)alkyl,aryl, heterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆alkyl or S(O)₂R^(a).
 4. The compound of claim 3, wherein R², R³, and R⁵are H.
 5. The compound of claim 4, wherein t is
 1. 6. The compound ofclaim 5 wherein R⁴ is selected from: 1) OC₁-C₆ alkyleneNR⁷R⁸, 2)(C═O)_(a)C₀-C₆ alkylene-Q, wherein Q is H, OH, CO₂H, or OC₁-C₆ alkyl, 3)OC₀-C₆ alkylene-heterocyclyl, optionally substituted with one to threesubstituents selected from R6^(a), 4) C₀-C₆ alkyleneNR⁷R⁸, 5)(C═O)NR⁷R⁸, and 6) OC₁-C₃ alkylene-(C═O)NR⁷R⁸.
 7. A compound selectedfrom: 6-Chloro-3-(1H-indol-2-yl)-1H-indazole3-(1H-Indol-2-yl)-1H-indazole 3-(1H-Indol-2-yl)-1H-indazol-5-ylamine3-(1H-Indol-2-yl)-6-methyl-1H-indazole3-(1H-Indol-2-yl)-4-chloro-1H-indazole3-(1H-Indol-2-yl)-7-chloro-1H-indazole3-(1H-Indol-2-yl)-4-fluoro-1H-indazole3-(1H-Indol-2-yl)-5-fluoro-1H-indazole3-(1H-Indol-2-yl)-5-methyl-1H-indazole3-(1H-Indol-2-yl)-6-trifluoromethyl-1H-indazole3-(1H-Indol-2-yl)-5,6-dimethyl-1H-indazole3-(1H-Indol-2-yl)-1H-indazole-6-sulfonic acid amide3-(1H-indol-2-yl)-1H-indazole-5-sulfonamide3-(1H-Indol-2-yl)-6-bromo-1H-indazole3-(1H-Indol-2-yl)-1H-indazole-6-carbonitrile3-[5-(piperazin-1-ylsulfonyl)-1H-indol-2-yl]-1H-indazole6-(2-Fluoro-pyridin-4-yl)-3(1H-indol-2-yl)-1H-indazole4-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H-pyridin-2-one3-(1H-Indol-2-yl)-6-(1-oxy-pyridin-3-yl)-1H-indazole3-(1H-Indol-2-yl)-6-(1H-pyrrol-2-yl)-1H-indazole3-(1H-Indol-2-yl)-6-(1H-pyrrol-3-yl)-1H-indazole5-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H-pyridin-2-one3-(1H-Indol-2-yl)-6-(1-oxy-pyridin-4-yl)-1H-indazole3-(1H-Indol-2-yl)-6-(1H-tetrazol-5-yl)-1H-indazole3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}-1H-indazole1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]-1-(4-methyl-piperazin-1-yl)-methanone1-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-yl]-1-piperazin-1-yl-methanone1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]-1-piperazin-1-yl-methanone2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide Methyl[2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-yl]sulfone2-(6-Chloro-1H-indazol-3-yl)-7-fluoro-1H-indole-5-sulfonic acid amide2-(6-Chloro-1H-indazol-3-yl)-6-fluoro-1H-indole-5-sulfonic acid amide2-(6-Chloro-1H-indazol-3-yl)-4-fluoro-1H-indole-5-sulfonic acid amide7-Chloro-2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide2-(6-Chloro-5-fluoro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-carboxylic acid methyl ester2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-carboxylic acid6-Chloro-3-(5-fluoro-1H-indol-2-yl)-1H-indazole6-Chloro-3-(5-methyl-1H-indol-2-yl)-1H-indazole3-[5-(4-Methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole p03-[5-(4-Methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole6-Chloro-3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole6-Chloro-3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole1-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-4-methyl-[1,4]diazepan-5-one1-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-2-hydroxy-ethanone3-{4-[2-(6-Chloro-1H-indazol-3yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-butyricacid6-Chloro-3-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-4-ylmethyl]-piperazin-1-yl}-butyricacid or a pharmaceutically acceptable salt or stereoisomer thereof.
 8. Acompound according to claim 7 selected from:2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide

6-Chloro-3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole

1-{(4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-2-hydroxy-ethanone

3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-butyricacid

6-Chloro-3-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole

or a pharmaceutically acceptable salt or stereoisomer thereof.
 9. Apharmaceutical composition which is comprised of a compound inaccordance with claim 1 and a pharmaceutically acceptable carrier.
 10. Amethod of treating or preventing cancer in a mammal in need of suchtreatment which is comprised of administering to said mammal atherapeutically effective amount of a compound of claim
 1. 11. A methodof treating cancer or preventing cancer in accordance with claim 10wherein the cancer is selected from cancers of the brain, genitourinarytract, lymphatic system, stomach, larynx and lung.
 12. A method oftreating or preventing cancer in accordance with claim 10 wherein thecancer is selected from histiocytic lymphoma, lung adenocarcinoma, smallcell lung cancers, pancreatic cancer, glioblastomas and breastcarcinoma.
 13. A method of treating or preventing a disease in whichangiogenesis is implicated, which is comprised of administering to amammal in need of such treatment a therapeutically effective amount of acompound of claim
 1. 14. A method in accordance with claim 13 whereinthe disease is an ocular disease.
 15. A method of treating or preventingretinal vascularization which is comprised of administering to a mammalin need of such treatment a therapeutically effective amount of compoundof claim
 1. 16. A method of treating or preventing diabetic retinopathywhich is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of compound of claim
 1. 17.A method of treating or preventing age-related macular degenerationwhich is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of claim 1.18. A method of treating or preventing inflammatory diseases whichcomprises administering to a mammal in need of such treatment atherapeutically effective amount of a compound of claim
 1. 19. A methodaccording to claim 18 wherein the inflammatory disease is selected fromrheumatoid arthritis, psoriasis, contact dermatitis and delayedhypersensitivity reactions.
 20. (canceled)
 21. (canceled)
 22. (canceled)23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled) 27.(canceled)
 28. A method of treating or preventing cancer which comprisesadministering a therapeutically effective amount of a compound of claim1 in combination with a compound selected from: 1) an estrogen receptormodulator, 2) an androgen receptor modulator, 3) retinoid receptormodulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) aprenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor,8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and10) another angiogenesis inhibitor.
 29. (canceled)
 30. (canceled) 31.(canceled)
 32. (canceled)
 33. (canceled)
 34. (canceled)
 35. (canceled)36. (canceled)
 37. (canceled)
 38. (canceled)
 39. (canceled)